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Knowledge-Based Design of Long-Chain Arylpiperazine Derivatives Targeting Multiple Serotonin Receptors as Potential Candidates for Treatment of Autism Spectrum Disorder

  • Enza Lacivita*
    Enza Lacivita
    Dipartimento di Farmacia−Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, via Orabona, 4, 70125 Bari, Italy
    *Email: [email protected]
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    Orcidhttp://orcid.org/0000-0003-2443-1174
  • , 
  • Mauro Niso
    Mauro Niso
    Dipartimento di Farmacia−Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, via Orabona, 4, 70125 Bari, Italy
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  • , 
  • Margherita Mastromarino
    Margherita Mastromarino
    Dipartimento di Farmacia−Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, via Orabona, 4, 70125 Bari, Italy
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  • Andrea Garcia Silva
    Andrea Garcia Silva
    Center for Research in Molecular Medicine and Chronic Diseases (CIMUS). Universidade de Santiago de Compostela. Avda. de Barcelona, s/n, 15782 Santiago de Compostela, Spain
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  • , 
  • Cibell Resch
    Cibell Resch
    Cellular Neurophysiology, Hannover Medical School, 30625 Hannover, Germany
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  • Andre Zeug
    Andre Zeug
    Cellular Neurophysiology, Hannover Medical School, 30625 Hannover, Germany
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  • María I. Loza
    María I. Loza
    Center for Research in Molecular Medicine and Chronic Diseases (CIMUS). Universidade de Santiago de Compostela. Avda. de Barcelona, s/n, 15782 Santiago de Compostela, Spain
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  • Marián Castro
    Marián Castro
    Center for Research in Molecular Medicine and Chronic Diseases (CIMUS). Universidade de Santiago de Compostela. Avda. de Barcelona, s/n, 15782 Santiago de Compostela, Spain
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  • Evgeni Ponimaskin
    Evgeni Ponimaskin
    Cellular Neurophysiology, Hannover Medical School, 30625 Hannover, Germany
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  • , and 
  • Marcello Leopoldo*
    Marcello Leopoldo
    Dipartimento di Farmacia−Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, via Orabona, 4, 70125 Bari, Italy
    *Email: [email protected]
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    Orcidhttp://orcid.org/0000-0001-8401-2815
Cite this: ACS Chem. Neurosci. 2021, 12, 8, 1313–1327
Publication Date (Web):April 1, 2021
https://doi.org/10.1021/acschemneuro.0c00647

Copyright © 2022 The Authors. Published by American Chemical Society. This publication is licensed under

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Abstract

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Autism spectrum disorder (ASD) includes a group of neurodevelopmental disorders characterized by core symptoms such as impaired social interaction and communication, repetitive and stereotyped behaviors, and restricted interests. To date, there are no effective treatments for these core symptoms. Several studies have shown that the brain serotonin (5-HT) neurotransmission system is altered in both ASD patients and animal models of the disease. Multiple pieces of evidence suggest that targeting 5-HT receptors may treat the core symptoms of ASD and associated intellectual disabilities. In fact, stimulation of the 5-HT1A receptor reduces repetitive and restricted behaviors; blockade of the 5-HT2A receptor reduces both learning deficits and repetitive behavior, and activation of the 5-HT7 receptor improves cognitive performances and reduces repetitive behavior. On such a basis, we have designed novel arylpiperazine derivatives pursuing unprecedently reported activity profiles: dual 5-HT7/5-HT1A receptor agonist properties and mixed 5-HT7 agonist/5-HT1A agonist/5-HT2A antagonist properties. Seventeen new compounds were synthesized and tested in radioligand binding assay at the target receptors. We have identified the dual 5-HT1AR/5-HT7R agonists 8c and 29 and the mixed 5-HT1AR agonist/5-HT7R agonist/5-HT2AR antagonist 20b. These compounds are metabolically stable in vitro and have suitable central nervous system druglike properties.

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Introduction

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Autism spectrum disorder (ASD) includes a group of brain developmental disorders characterized by core symptoms such as impaired social interaction and communication, repetitive and stereotyped behaviors, and restricted interests. (1) In addition, ASD patients often present a variety of additional impairments, including intellectual disability. The frequency of ASD is increasing, with present rates of about 1 in 100 children in Europe and 1 in 54 in the United States. (2) To date, the only drugs approved to treat ASD-related symptoms are the atypical antipsychotics aripiprazole and risperidone (Table 1) which are efficacious to treat irritability, hyperactivity, and aggression but not the core symptoms. Thus, ASD has no cure and its treatment represents a largely unmet clinical need. (3) Several mechanisms have been implicated in ASD, such as synaptic dysfunction (alterations in dendritic spine morphology, excitatory/inhibitory imbalance), neuroinflammation, and altered neurotransmitter systems. (3) Serotonin (5-hydroxytryptamine, 5-HT) exerts a very complex modulatory role in the central nervous system (CNS) involving at least 14 diverse membrane 5-HT receptors (5-HTRs), grouped in seven families (5-HT1–7). 5-HT plays a crucial role in shaping neuronal circuits during prenatal and postnatal development by promoting neurogenesis, neuronal differentiation, axon myelination, neuropil formation, and synaptogenesis. (4,5) Accumulating findings indicate that the brain 5-HT neurotransmission system is altered in ASD patients (6) and in rodent models of ASD. (7−9) Selective serotonin reuptake inhibitors (SSRIs) have been often prescribed to ASD patients to treat repetitive and stereotyped behaviors as these drugs are efficacious to treat obsessive-compulsive disorder. However, clinical studies in ASD patients treated with SSRIs did not give consistent results. (10) In fact, some studies reported positive effects on stereotypy and compulsions, whereas others reported that SSRIs worsen stereotypy. In addition, side-effects were highly prevalent probably due to the generalized elevation of 5-HT levels that could lead to not therapeutically valid stimulation of multiple 5-HTRs. Various studies have evidenced that targeting certain 5-HTRs has the potential to treat the core symptoms of ASD and associated intellectual disabilities. A clinical trial in young children with ASD demonstrated that the 5-HT1AR partial agonist buspirone reduces repetitive and restricted behaviors. (11) Studies in rodent models of ASD have provided further support in this direction. In fact, buspirone and the 5-HT1AR full agonist 8-OH-DPAT enhance social interactions. (12,13) The selective 5-HT2AR antagonist M100907 alleviates both learning deficits and repetitive behavior. (14,15) The selective 5-HT6R antagonist SLV reverses the social engagement deficit. (16) The selective 5-HT7R agonist LP-211 (Table 1) corrects behavioral alterations in mouse models of rare neurodevelopmental disorders. In particular, administration of LP-211 (i) improved novel object recognition performance and reduced stereotyped behavior in a mouse model of Fragile-X syndrome (an X-linked disease with autistic features); (17−19) (ii) improved anxiety-related profiles, the exploratory behavior and memory in a mouse model of Rett syndrome (a disease characterized by intellectual disability); (20−22) and (iii) normalized the prepulse inhibition defects observed in a mouse model of CDKL5 deficiency disorder (a disease characterized by severe neurodevelopmental delay impacting cognitive, speech, and visual function). (23) Altogether, the above studies provide support to the search of novel compounds with an appropriate pharmacological profile at 5-HTRs in the prospect to ameliorate the core symptoms of ASD. At present, various examples of drugs or investigational compounds targeting multiple 5-HTRs exist. The most notable examples are aripiprazole (dopamine D2R/5-HT2AR/5-HT7R antagonist, 5-HT1AR partial agonist) and risperidone (dopamine D2R/5-HT2AR/5-HT7R/5-HT1AR antagonist) (Table 1). (24) However, aripiprazole and risperidone are not effective on the core symptoms of ASD, suggesting that such particular activity profile is not suitable to treat the core symptoms of ASD. (3) Vortioxetine, a multimodal antidepressant that inhibits 5-HT transporter and activates 5-HT1A and 5-HT1B receptors, suppresses restrictive–repetitive behaviors in a rodent model of ASD but has less efficacy as a sociability enhancer. (25) These studies strongly suggest the design of new compounds characterized by an activity profile resulting from combinations of activities at 5-HTRs that are predicted to produce effects on the core symptoms of ASD. The first attempt in this direction was reported in 2015 by Canal et al., who developed the compound (+)-5-FPT which was initially described as a high-affinity 5-HT7R and 5-HT1AR partial agonist (Table 1). The (+)-5-FPT potently attenuated stereotypy in three heterogeneous models of stereotypy in a mouse strain characterized by repetitive behavior. (26) In 2020, the same research group reported that (+)-5-FPT was actually a 5-HT1AR/5-HT2CR agonist and 5-HT7R antagonist. (27) This compound was then studied in a mouse model of Fragile X syndrome and found to reduce repetitive behavior through 5-HT1AR partial agonism and to attenuate audiogenic seizure through 5-HT2CR agonism. Thus, the potential of concomitant activation of 5-HT1AR and 5-HT7R was not actually explored.
Table 1. Structural Formulas and Affinity Profiles of the Reference Compounds
a

Not Available.

Therefore, on the basis of the data discussed above, we aimed at identifying completely new modulators of 5-HTRs for studies in the context of ASD. In particular, we searched for (a) a dual 5-HT7R/5-HT1AR agonist, which is predicted to increase social interaction through the activation of 5-HT1AR and to reduce stereotypy and improve cognition through activation of 5-HT7R, and (b) a compound acting as 5-HT7R/5-HT1AR agonist and 5-HT2AR antagonist, which is predicted to improve social behavior through activation of 5-HT1AR, to reduce or eliminate stereotyped behavior by blocking 5-HT2AR, and to improve cognition through activation of 5-HT7R.

Results and Discussion

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Study Design

Long-chain arylpiperazine derivatives are known to bind monoamine receptors, including 5-HTRs. The general formula is Ar–piperazine–linker–terminal fragment, and it is known that suitable modifications of Ar, linker, or terminal fragment can lead to selective or nonselective compounds. Two examples of selective arylpiperazine ligands are the 5-HT1AR antagonist WAY-100635 and the 5-HT7R agonist LP-211 (28) (Table 1). Instead, compounds 1 (29) and 2 (30) (Table 1) are dual 5-HT7R/5-HT1AR ligands, and compound 3 (31) is a mixed 5-HT7R/5-HT1AR/5-HT2AR ligand (Table 1). Thus, long-chain arylpiperazines are a versatile framework to identify compounds with a diversified receptor affinity profile. On the other hand, it appears much less trivial to identify arylpiperazines showing the activity profile that we are pursuing (i.e., dual 5-HT7R/5-HT1AR agonist, mixed 5-HT7R agonist/5-HT1AR agonist/5-HT2AR antagonist). To fulfill our aim, we have followed a knowledge-based design (i.e., the collection and reuse of expert knowledge) by selecting Ar groups and terminal fragments present in arylpiperazine-based 5-HTR agonists or antagonists. First, we focused on the Ar group and selected the 1-(biphenyl)piperazine moiety that is the key structural determinant for the agonism at 5-HT7R of LP-211, TP-22, (32) and BA-10 (18) (Table 1). Consequently, the majority of the target compounds are 1-[2-(4-methoxyphenyl)phenyl]piperazine derivatives (see Table 2). In addition, in order to identify dual 5-HT7R/5-HT1AR ligands, the compounds 9 and 30 (Table 2), featuring the 2-acetylphenyl group present in the dual 5-HT7R/5-HT1AR ligand 1 (Table 1), were designed. It is worth noting that, even if LP-211, TP-22, and BA-10 are 5-HT7R-preferring agonists, they still show a measurable affinity for 5-HT1AR (Table 1). Interestingly, LP-211 itself shows measurable 5-HT2AR affinity (Table 1). (28) Thus, the 1-(biphenyl)piperazine framework appears to be compatible with 5-HT1AR and 5-HT2AR affinity, and therefore, suitable variations of the terminal fragments and linkers might increase 5-HT1AR and 5-HT2AR affinity. In the case of 5-HT1AR, the terminal fragment also has a role on the functional activity of the ligand. With this respect, notable examples are the 2-methoxyphenyl piperazine derivatives WAY-100635, (33)4, (34) and MMP. (35) In fact, while WAY-100635 is a 5-HT1AR antagonist, compounds 4 and MMP are agonists. Consequently, we have selected the terminal fragments present in the high-affinity 5-HT1AR agonists MMP (which also shows 5-HT7R affinity in the nanomolar range) and UCM-2550 (36) (Table 1). As for 5-HT2AR, we selected the terminal fragments of the antagonists risperidone, brilaroxazine, (37) and 5 (38) (Table 1). Based on the structural similarity with these antagonists, our newly designed arylpiperazine derivatives were expected to act as 5-HT2AR antagonist, as they display a completely different structural motif as compared to that of 5-HT2AR agonists. (39) The fine-tuning of the affinities at the target receptors was accomplished by incorporating 2–5 atom linkers.
Table 2. CNS MultiParameter Optimization (CNS-MPO), Binding Affinities, Ki Ratios, and Microsomal Stability of the Target Compounds
a

MS: microsomal stability (% of recovery of the parent compound after 30 min incubation with rat microsomes).

b

Full displacement of the specific binding was not achieved at maximum concentration assayed (100 μM); Ki value extrapolated from the analysis might not be accurately estimated;

c

Data from ref (51).

In addition, the drug-likeness CNS multiparameter optimization (CNS MPO) algorithm (40) was applied to the designed compounds. As shown in Table 2, 7 out of 17 compounds present a CNS MPO desirability score higher than 4, predictive of alignment to ADME attributes, ability to cross the blood–brain barrier, and low safety risk. As for the remaining compounds, 8 out 10 show CNS MPO desirability score in the range of 3 to 4 which might still include compounds with desirable properties.
In order to evaluate the liability of the target compounds to metabolic degradation by first-pass oxidative metabolism, the main cause of metabolic degradation in vivo, we screened the metabolic stability in vitro by using rat liver microsomes. (41) First, the metabolic stability was assessed as the percentage of the parent compound recovered after 30 min of incubation with microsomes in the presence of an NADPH-regenerating system. (32) Subsequently, selected compounds showing recovery higher than 20% were further characterized by evaluating half-life (t1/2) and intrinsic clearance (CLint), which are predictive of in vivo hepatic clearance.

Chemistry

The target compounds 8a–c and 9 bearing the 4-methyl-1,2,4-triazine-3,5(2H,4H)-dione moiety as the terminal fragment were prepared according to Scheme 1. 4-Methyl-1,2,4-triazine-3,5(2H,4H)-dione (6) (42) was alkylated with the appropriate haloalkylbromide to give the alkyl halides 7a–c, which after nucleophilic substitution with the appropriate arylpiperazine, afforded the desired compounds 8a–c and 9.

Scheme 1

Scheme 1. Synthesis of Target Compounds 8a–c and 9a
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aReagents and conditions: (A) NaH, Br–(CH2)n–X, anhydrous DMF, rt, 12 h, 40–70% yield; (B) 1-arylpiperazine; K2CO3, acetonitrile, reflux overnight, 20–50% yield.

Scheme 2 illustrates the synthesis of target compounds 11a,b. Compound 11a was obtained by reacting 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (10) (43) with 1-[2-(4-methoxyphenyl)phenyl]piperazine. (44) Compound 11b was obtained through a convergent synthesis that required intermediates 13 and 16 (Scheme 2). Amine 13 was synthesized starting from alkyl chloride 10 by sequential reaction with cyanide ion to give the nitrile 12 and reduction of the latter with Raney nickel under hydrogen pressure. Bromide 16 was prepared from 2-(4-methoxyphenyl)aniline (14) (44) and 2-bromoethanol in the presence of CaCO3 to afford the bis alkylated product 15, which was converted into 16 with PBr3. Condensation of the amine 13 and the bromide 16 yielded the target compound 11b.

Scheme 2

Scheme 2. Synthesis of Target Compounds 11a,ba
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aReagents and conditions: (A) 1-[2-(4-methoxyphenyl)phenyl]piperazine; K2CO3, acetonitrile, reflux overnight, 61% yield; (B) NaCN, anhydrous DMF, rt, 5 h, quantitative yield; (C) Raney-nickel, H2 (4 atm), MeOH, 50% yield; (D) 2-bromoethanol, CaCO3; reflux, 7 h, 37% yield; (E) PBr3, anhydrous toluene, reflux, 3 h, 65% yield; (F) K2CO3, acetonitrile, reflux overnight, 60% yield.

The target compounds featuring the coumarin nucleus as the terminal fragment were prepared as described in Scheme 3. In order to synthesize compound 20a from compound 19a, several unsuccessful attempts were made to alkylate 7-hydroxy-4-methylcoumarin (18) (45) with 1-bromo-2-chloroethane. Then, compound 19a was instead synthesized starting from 3-(2-bromoethoxy)phenol (17), (46) which was condensed with ethyl acetoacetate under Pechmann conditions. Nucleophilic substitution of 19a by 1-[2-(4-methoxyphenyl)phenyl]piperazine afforded the desired compound 20a. The analogues 20b,c were prepared starting from phenol 18 which was alkylated with the appropriate bromoalkylchloride to afford derivatives 19b,c. These latter compounds were condensed with 1-[2-(4-methoxyphenyl)phenyl]piperazine to give the desired compounds 20b,c, respectively.

Scheme 3

Scheme 3. Preparation of Target Compounds Featuring the Coumarin Nucleus as the Terminal Fragmenta
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aReagents and conditions: (A) ethyl acetoacetate; conc. H2SO4, rt, 4 h, 34% yield; (B) 1-[2-(4-methoxyphenyl)phenyl]piperazine; K2CO3, acetonitrile, reflux overnight, 21% yield; (C) NaH, Br–(CH2)n–X, anhydrous DMF, rt, 12 h, 40–60% yield.

The final compounds 26a,b, 29, and 30 featuring the benzoxazinone terminal fragment were prepared following two distinct synthetic routes depending on the nature of the linker (Schemes 4 and 5). In fact, the synthesis of the key intermediate 25a was initially pursued through alkylation of 6-hydroxy-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (27) with 1-bromo-2-chloroethane, but it was unsuccessful. Thus, an alternative synthetic pathway was envisaged (Scheme 4): 4-(benzyloxy)-2-nitrophenol (21) (47) was alkylated with methyl 2-bromopropanoate to afford derivative 22, which was deprotected under basic conditions to give phenol 23. The latter was alkylated with 1,2-dibromoethane to give 24. Reduction of the nitro group of 24 by iron dust in acidic conditions resulted in the cyclization of the intermediate amine to give the key intermediate 25a, which was condensed with 1-[2-(4-methoxyphenyl)phenyl]piperazine to give the target compound 26a. The other target compound 26b bearing the benzoxazinone nucleus as terminal fragment was prepared according to Scheme 5. Alkylation of phenol 27 (48) with 1-bromo-3-chloropropane gave the chloroderivative 25b, which underwent nucleophilic substitution with 1-[2-(4-methoxyphenyl)phenyl]piperazine to give the final compound 26b. The target compounds 29 and 30 were prepared starting from phenol 27 which was alkylated with (R)-glycidylnosilate to give oxirane 28. Ring opening of 28 with the appropriate 1-arylpiperazine gave 29 and 30.

Scheme 4

Scheme 4. Synthetic Route to Obtain Final Compounds 26aa
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aReagents and conditions: (A) methyl 2-bromopropionate, K2CO3, acetone, reflux, 16 h, 54% yield; (B) CH3ONa, MeOH, rt, 3 h, 89% yield; (C) 1,2-dibromoethane, K2CO3, anhydrous DMF, 85 °C, 6 h, 70% yield; (D) Fe dust, AcOH, 80 °C, 1 h, 60% yield; (E) 1-[2-(4-methoxyphenyl)phenyl]piperazine; K2CO3, acetonitrile, reflux overnight, 38% yield.

Scheme 5

Scheme 5. Synthetic Route to Obtain Final Compounds 26b, 29, and 30a
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aReagents and conditions: (A) NaH, Br–(CH2)3–Cl, anhydrous DMF, rt, 24 h, 22–42% yield; (B) 1-[2-(4-methoxyphenyl)phenyl]piperazine; K2CO3, acetonitrile, reflux overnight, 20–65% yield. (C) NaH, (R)-glycidyl nosilate, anhydrous DMF, rt, overnight, 41% yield; (D) 1-arylpiperazine; EtOH, reflux, 4 h, 30–54% yield.

The target compounds bearing the tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione as terminal fragment were prepared according to Scheme 6. The N-alkylation of hydantoin derivative 31 (49) with the appropriate bromoalkylchloride gave the chloroalkyl intermediates 32a,b, which were condensed with 1-[2-(4-methoxyphenyl)phenyl]piperazine to afford the desired compounds 33a,b, respectively.

Scheme 6

Scheme 6. Formation of Target Compounds Bearing the Tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione as Terminal Fragmenta
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aReagents and conditions: (A) NaH, Br–(CH2)n–Cl, anhydrous DMF, rt, 12 h, 55–75% yield; (B) 1-[2-(4-methoxyphenyl)phenyl]piperazine; K2CO3, acetonitrile, reflux overnight, 43–74% yield.

Binding Affinities to 5-HT7, 5-HT1A, 5-HT2A, and Dopamine D2 Receptors

All the final compounds were tested in radioligand binding assays to determine their affinity for 5-HT7R, 5-HT1AR, and 5-HT2AR (Table 2). In addition, the compounds were counter screened at dopamine D2 receptors, because blockade of this receptor may cause motor dysfunctions. (50) The assays were performed via the displacement of the specific binding of [3H]-5-CT (for 5-HT7R), [3H]-8-OH-DPAT (for 5-HT1AR), [3H]ketanserin (for 5-HT2AR), and [3H]spiperone (for dopamine D2 receptor), at the cloned human receptors stably expressed in HEK293 cells (5-HT7R, 5-HT1AR) or CHO-K1 cells (5-HT2AR, D2 receptor).
The Ki values at 5-HT7R of the target 1-[2-(4-methoxyphenyl)phenyl]piperazine derivatives 8a,b, 11a,b, 20a–c, 26a–c, 29, and 33a,b are in the range 6.69–91.7 nM, indicating that the structural variations introduced to the terminal fragment or linker of LP-211 were well tolerated. In fact, such variations translate into small changes in affinity, the largest variation being in the case of 33a and 33b (7-fold). Of note, the 5-HT7R affinity values of the reference compounds brilaroxazine (vs 26a–c, 29), UCM-2550 (vs 33a,b), risperidone (vs 11a,b), and MMP (vs 8a–c) fell in the same range. Instead, the 1-(2-acetylphenyl)piperazine derivatives 9 and 30 were 50- and 11-fold less potent than the reference compound 1 at 5-HT7R.
As for the 5-HT1AR affinities, the 1-(2-acetylphenyl)piperazine derivatives 9 and 30 were equipotent potent to the reference compound 1, whereas the target 1-[2-(4-methoxyphenyl)phenyl]piperazine derivatives 8a,b, 11a,b, 20a–c, 26a–c, 29, and 33a,b showed Ki values distributed in a wide range (3.77–1802 nM), as the result of a more pronounced impact of the linker length. In fact, the 4-methyl-1,2,4-triazine-3,5(2H,4H)-dione derivative 8c displays Ki = 3.77 nM, whereas its shorter homologue 8a shows a 456-fold lower 5-HT1AR affinity. Similarly, the benzoxazinone derivative 26b displays Ki = 23.2 nM, whereas its shorter homologue 26a shows 78-fold lower affinity. The comparison of the close analogs 26a–c, 29, and 34 provides an interesting example of how the affinity for 5-HT7R and 5-HT1AR can be fine-tuned by the nature of the terminal fragment and the linker. It can be noted that the target compounds 26a–c, 29 (vs brilaroxazine), 33a,b (vs UCM-2550), 8a–c (vs MMP), and 20a–c (vs 5) display lower 5-HT1AR affinity than that of the reference compounds featuring the corresponding terminal fragment. Nonetheless, the proposed structural changes led to the identification of six compounds (8c, 11a, 20b, 26b,c, and 33b) with 5-HT1AR affinity higher than that of LP-211.
Considering the affinity at 5-HT2AR, all the target 1-[2-(4-methoxyphenyl)phenyl]piperazine derivatives show affinity higher than that of LP-211, except 8a and 33a, confirming the validity of the selection of terminal fragments present in the reference compounds. Compounds 8a and 33a represent an unfavorable combination of linker length and terminal fragment. The most pronounced increase was in the case of compound 11b in which the terminal fragment is the same as in risperidone. The 5-HT2AR affinity of the final 1-(2-acetylphenyl)piperazine derivatives 9 and 30 was in the micromolar range, which was similar to the affinity value of the corresponding reference compound 1.
The D2 receptor affinities of the target 1-[2-(4-methoxyphenyl)phenyl]piperazine derivatives were all lower than that of LP-211, but 26c that displayed a Ki value lower than 100 nM. Most importantly, the reference compounds risperidone (vs 11a,b), 5 (vs 20a–c), brilaroxazine (vs 26a–c, 29), and UCM-2550 (vs 33a,b) show higher D2 receptor affinity than that of the target compounds featuring the corresponding terminal fragment. Thus, the affinity of the target compounds at D2 receptors seems to be determined by the 1-[2-(4-methoxyphenyl)phenyl]piperazine moiety rather than the linker length and the terminal fragment. As for the 1-(2-acetylphenyl)piperazine derivatives 9 and 30, both compounds showed high D2 receptor affinity, being the most potent D2 receptor ligands among the newly synthesized compounds.
Next, in order to select dual 5-HT7R/5-HT1AR or mixed 5-HT7R/5-HT1AR/5-HT2AR ligands, we analyzed the 5-HT1AR/5-HT7R, 5-HT2AR/5-HT7R, and 5-HT2AR/5-HT1AR Ki ratios (Table 2). As reference values, we selected the Ki ratios of compound 26c which, according to our recent study, behaved as a 5-HT7R-preferring agonist in vitro and in vivo. (51) Consequently, to select the dual 5-HT1AR/5-HT7R ligands, we considered compounds showing a 5-HT1AR/5-HT7R Ki ratio lower than 9 (and greater than 0.11, i.e., the reciprocal of 9). Compounds 8c, 29, and 30 displayed such characteristic. These compounds were also selective over 5-HT2AR. The most balanced 5-HT1AR/5-HT7R ligands of this set were 8c and 29, as they showed the 5-HT7R/5-HT1AR Ki ratios closest to 1. On the other hand, compounds 20b, 20c, 26b, and 34 displayed mixed 5-HT7R/5-HT1AR/5-HT2AR affinity, with 20b being the compound with the most balanced affinity profile (all three Ki ratios close to 1).

In Vitro Metabolic Stability

The aim of this study is to provide the scientific community with molecules suitable for studies in vivo. In order to predict the extent of first-pass oxidative metabolism, the target compounds were incubated with rat liver microsomes in the presence of an NADPH regenerating system. (41) In the initial screening phase, we assessed the percentage of the parent compound recovered after 30 min of incubation. The percentages of recovery of LP-211 and TP-22 were 20 and 27%, respectively, (32) which represented the reference values to compare the new compounds. As it can be seen in Table 1, the majority of the new compounds show in vitro stability higher than LP-211, as 11 out of 17 compounds display a percentage of recovery >20%. Then, taking into account the affinity, selectivity, and metabolic stability data, we assessed the half-life and the intrinsic clearance in vitro of compounds 8c, 20b,c, 26a,b, and 29 (Table 3). The data indicate that all the selected compounds showed higher stability than that of LP-211, with intrinsic clearance values lower up to 5-fold as in the case of compound 29. Thus, the compounds listed in Table 3 are predicted to be low-clearance compounds and suitable for studies in vivo. (52) These results provide further support to the strategy of using structural motifs featured by druglike compounds to obtain metabolically stable compounds. (40,51)
Table 3. Half-Life (t1/2) and Intrinsic Clearance (CLint) of Selected Compounds
compoundt1/2 (min)CLint (μL/mg/min)
LP-211 (32)1545.9
TP-22 (32)4516.1
8c4116.9
20b3917.7
20c2330
26a4914.1
26b6011.5
26c (51)6311
29749.4
34 (51)5812
The metabolic stability and the affinity data supported the selection of the dual 5-HT7R/5-HT1AR ligands 8c and 29 and the mixed 5-HT7R/5-HT1AR/5-HT2AR ligand 20b for further evaluations. These compounds distinguished themselves from the reference compounds for the binding profile at 5-HT7, 5-HT1A, 5-HT2A, and D2 receptors. As shown in Table 1, most of the reference compounds display an affinity for α1A adrenoceptor, and therefore, it was not unexpected that compounds 8c, 20b, and 29 showed α1A adrenoceptor affinity (Ki= 23.5, 66.1, and 55.8 nM, respectively, see Supporting Information). In fact, the search for arylpiperazine derivatives with affinity for multiple 5-HTRs might imply that the compounds have an affinity for other monoamine receptors (see Supporting Information for off-target affinities of compounds 8c, 20b, and 29). Considering that α1A adrenoceptor activity might cause cardiovascular side-effect, this particular off-target activity is a safety warning for future developments of this class of compounds.

Functional Activities at 5-HT7R, 5-HT1AR, and 5-HT2AR of Compounds 8c, 20b, and 29

To provide a functional analysis at 5-HT7R, the cAMP response mediated by 8c, 20b, 29 and the reference 5-HT7R agonists 5-CT and LP-211 (29,53) was analyzed. To this end, 5-HT7R-mCherry was coexpressed with the FRET-based cAMP biosensor CEPAC. (54) This biosensor includes the cAMP-binding domain of the EPAC protein cloned between mCerulean (FRET donor) and Citrine (FRET acceptor). Upon cAMP binding, conformational changes of the sensor occur, leading to a decrease in the FRET signal (Figure 1A). The cAMP responses were recorded at the single-cell level by monitoring the CEPAC fluorescence intensity ratio of the acceptor to the donor (A/D ratio). The strength and speed of serotonergic signaling was determined from the amplitude and time dependence of the CEPAC fluorescence intensity ratio.

Figure 1

Figure 1. Compounds 8c, 20b, and 29 stimulate 5-HT7R-mediated cAMP production. (A) N1E cells were transfected with cAMP FRET-based biosensor CEPAC and 5-HT7R-mCherry. Cells were stimulated with the compounds, as indicated. Mean values of the cAMP-biosensor response upon stimulation with 8c 20b, and 29 are shown. Stimulation with LP-211 and 5-CT was used as a control. (B) Quantification of the response amplitude and (C) response time shown as the mean ± SEM (3 < N < 6, in each experiment at least 20 cells were analyzed).

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In the absence of 5-HT7R, no cAMP response was observed upon treatment with the ligands (data not shown). In contrast, in cells expressing 5-HT7R, all the compounds (10 μM) were able to increase the intracellular cAMP level, although with different efficiencies. Statistical analysis by fitting the experimental data to the single exponential revealed that 8c and 29 elicited the largest cAMP response amplitude compared with that of 5-CT, followed by 20b (Figure 1A). Of note, response amplitude for all compounds tested was higher than that measured for highly selective 5-HT7R agonist LP-211 (Figure 1B). The mean response times for all compounds were higher (i.e., slower response kinetics) than that obtained for 5-CT and comparable with the values obtained for LP-211 (Figure 1C).
We next analyzed whether 8c, 20b, and 29 would affect the 5-HT1AR function toward cAMP inhibition. The 5-HT1AR agonist 5-CT was used as a positive control, (55) while LP-211 (selective 5-HT7R agonist) was used as a negative control. To this end, 5-HT1AR-mCherry was coexpressed with the CEPAC biosensor in N1E cells. We subsequently analyzed the ability of 5-HT1AR-mediated signaling via Gi to inhibit the forskolin (FSK)-induced cAMP accumulation following receptor stimulation with above-mentioned compounds (10 μM). Except for LP-211 treatment, an increase of the A/D ratio of CEPAC was observed in all the cases, that indicated the 5-HT1AR-mediated downregulation of intracellular concentration of cAMP (Figure 2). Statistical evaluation of amplitudes of the cAMP decay for 8c, 20b, and 29 revealed that, although these compounds were still able to evoke receptor-mediated decrease of the concentration of cAMP, they were less effective in activation of 5-HT1AR when compared with 5-CT (Figure 2B).

Figure 2

Figure 2. Compounds 8c, 20b, and 29 behave as 5-HT1AR agonists in the receptor-mediated cAMP inhibition. (A) N1E cells were transfected with cAMP FRET-based biosensor CEPAC and 5-HT1AR-mCherry. After pretreatment with 1 μM forskolin and 25 μM IBMX, cells were stimulated with the indicated compounds. Each trace shows cAMP response at the single cell. (B) Graphs show changes of cAMP response amplitude relative to pretreatment (mean ± SEM, 3 < N < 6, in each experiment at least 20 cells were analyzed).

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Finally, compounds 8c, 20b, and 29 were investigated in functional assays of 5-HT2AR-mediated inositol phosphate (IP) signaling in CHO-K1 cells expressing the cloned human receptor. The three compounds, in concentration–response curves from 1 nM to 100 μM, fully antagonized in a concentration-dependent manner the stimulation of IP production elicited by 1 μM 5-HT (Figure 3). Consistently, no agonist activity was observed for 20b at the same concentrations in these assays (data not shown). IC50 values were similar for the three compounds and in the nanomolar range, consistent with their affinities at 5-HT2AR (IC50 = 595, 666, and 491 nM for 8c, 20b, and 29, respectively). The reference 5-HT2AR antagonist risperidone (0.01 nM–10 μM) showed a IC50 value of 0.81 nM (Figure 3).

Figure 3

Figure 3. Functional assays of inositol phosphate (IP) signaling at cloned human 5-HT2ARs. Concentration–response inhibition curves of 8c, 20b, 29, and risperidone (as reference 5-HT2AR antagonist) on IP production stimulated by 1 μM 5-HT in CHO-K1 cells expressing human 5-HT2ARs. The graph shows data (mean ± SEM) from one experiment performed in duplicate.

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Collectively, the functional activities of the selected compounds supported the validity of the design approach. In fact, compounds 8c, 20b, and 29 behave as 5-HT7R agonists in the same way as LP-211–confirming that the 1-(biphenyl)piperazine moiety is a key structural determinant for 5-HT7R agonism and as 5-HT2AR antagonists as various other arylpiperazine derivatives. As for 5-HT1AR, the comparison of the functional activities of 8c, 20b, and 29 with LP-211 suggest that the 1-(biphenyl)piperazine moiety alone is not responsible for the functional activity at 5-HT1AR, which, instead, is determined also by the nature of the terminal fragment and linker length, as already noted in the Study Design paragraph.

Conclusions

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5-HT neurotransmission system is an active area of investigation in ASD research. Several in vitro and in vivo studies with selective 5-HTR agonists or antagonists have suggested that targeting a subpopulation of the 5-HTRs might alleviate the core symptoms of ASD. Based on the current knowledge, we aimed at identifying a dual 5-HT7R/5-HT1AR agonist and a mixed 5-HT7R/5-HT1AR agonist/5-HT2AR antagonist. A set of novel arylpiperazine derivatives were designed by exploiting structural motifs that might drive the functional activity of the target compounds toward the desired profile (knowledge-based design). The design strategy succeeded as we identified compounds 8c and 29 that are 5-HT7R and 5-HT1AR preferring agonists and compound 20b, a mixed 5-HT7R/5-HT1AR agonist/5-HT2AR antagonist with almost identical affinity for the three receptors. The knowledge-based design strategy had a favorable influence on the in vitro pharmacokinetic properties of most of the newly designed compounds. In fact, 8c, 20b, and 29 are metabolically stable in vitro and also have suitable CNS druglike properties. Considering the complex mechanisms underlying ASD, we believe that a polypharmacology approach might be more suited than a single target approach. We hope that pharmacological tools such as 8c, 20b, and 29 will contribute to the progress of the discovery of drugs for ASD.

Methods

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Chemistry

Chemicals were purchased from Sigma-Aldrich, Alfa Aesar, TCI Chemicals. Unless otherwise stated, all chemicals were used without further purification. Thin layer chromatography (TLC) was performed using plates from Merck (silica gel 60 F254). Column chromatography was performed with 1:30 Merck silica gel 60 Å (63–200 μm) as the stationary phase. Flash chromatographic separations were performed on a Biotage SP1 purification system using flash cartridges prepacked with KP-Sil 32–63 μm, 60 Å silica. 1H NMR spectra were recorded on a Varian Mercury-VX spectrometer (300 MHz) or on a 500-vnmrs500 Agilent spectrometer (500 MHz). All chemical shift values are reported in parts per million (ppm, δ). Splitting patterns are designated as follows: app (apparent), br (broad), s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), td (triplet of doublets). For target compounds, NMR spectra were recorded on free bases. Recording of mass spectra was done on an HP6890-5973 MSD gas chromatograph/mass spectrometer; only significant m/z peaks, with their percentage of relative intensity in parentheses, are reported. ESI-MS/MS analyses were performed with an Agilent 1100 Series LC-MSD trap System VL workstation, mass range 50–800 m/z, electrospray ion source in positive or negative ion mode. All spectra were in accordance with the assigned structures. Elemental analysis (C,H,N) of the target compounds as hydrochloride salts were performed on a Eurovector Euro EA 3000 analyzer. Analyses indicated by the symbols of the elements were within ±0.4% of the theoretical values. The purity of the target compounds listed in Table 2 was assessed by RP-HPLC and combustion analysis. All compounds showed ≥95% purity. RP-HPLC analysis was performed on an Agilent 1260 Infinity Binary LC System equipped with a diode array detector using a Phenomenex Gemini C-18 column (250 mm × 4.6 mm, 5 μm particle size). All target compounds (Table 2) were eluted with CH3CN/ammonium formate 50 mM pH 5, 8:2 (v/v) at a flow rate of 1 mL/min. All compounds showed ≥95% purity.
The following compounds were prepared as described in the literature: 1-[2-(4-methoxyphenyl)phenyl]piperazine; (46) 1-(2-(piperazin-1-yl)phenyl)ethanone; (56) 4-methyl-1,2,4-triazine-3,5(2H,4H)-dione (6); (43) 2-(4-chlorobutyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione (7c); (43) 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (10); (44) 4′-methoxy-[1,1′-biphenyl]-2-amine (14); (46) 3-(2-bromoethoxy)phenol (17); (45) 7-hydroxy-4-methyl-chromen-2-one (18); (47) 4-(benzyloxy)-2-nitrophenol (21); (48) 6-[3-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]butoxy]-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (26c); (51) 6-hydroxy-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (27); (49) tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione (31); (50) (R)-1-(4-chloro-2-fluorophenoxy)-3-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]propan-2-ol (34). (51) Complete synthetic procedures and intermediated spectroscopic data are fully reported in the Supporting Information.

General Procedure for the Preparation of Target Compounds 8a–c, 9, 11a,b, 20a–c, 26a,b, and 33a,b

A stirred mixture of the appropriate alkylating agent (0.7 mmol), 1-[2-(4-methoxyphenyl)phenyl]piperazine or 1(2-acetylphenyl)piperazine (0.84 mmol), and K2CO3 (0.1 g, 0.7 mmol) in acetonitrile (20 mL) was refluxed overnight. After cooling, the mixture was evaporated to dryness, and H2O (20 mL) was added to the residue. The aqueous phase was extracted with AcOEt (2 × 30 mL). The collected organic layers were dried over Na2SO4 and evaporated under reduced pressure. The crude residue was purified by chromatographic column as detailed below to afford pure target compound.

2-{4-[4-[2-(4-Methoxyphenyl)phenyl]piperazin-1-yl]ethyl}-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione (8a)

Eluted with CHCl3/MeOH, 98:2. Yellow oil, 73% yield. 1H NMR (CDCl3): δ 2.43 (br s, 4H), 2.67 (t, 2H, J = 6.6 Hz), 2.80 (br s, 4H), 3.32 (s, 3H), 3.85 (s, 3H), 4.08 (t, 2H, J = 6.6 Hz), 6.91–6.93 (m, 2H), 7.00 (d, 1H, J = 7.8 Hz), 7.04 (td, 1H, J = 1.1 and 7.6 Hz), 7.21 (dd, 1H, J = 1.5 and 7.3 Hz), 7.26 (m, 1H), 7.37 (s, 1H), 7.55–7.57 (m, 2H). GC/MS m/z 422 (M+, 4), 421 (M+, 16), 281 (100). Anal. (C23H27N5O3·HCl·H2O) C, H, N.

2-{3-[4-[2-(4-Methoxyphenyl)phenyl]piperazin-1-yl]propyl}-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione (8b)

Eluted with CHCl3/EtOAc, 1:1. Brown oil, 40% yield. 1H NMR (CDCl3): δ 1.88–1.92 (m, 2H), 2.34 (br s, 4H), 2.40 (t, 2H, J = 7.0 Hz), 2.80 (br s, 4H), 3.32 (s, 3H), 3.85 (s, 3H), 4.03 (t, 2H, J = 7.0 Hz), 6.92 (d, 2H, J = 8.8 Hz), 6.98–7.05 (m, 2H), 7.02–7.07 (m, 1H), 7.19–7.22 (m, 1H), 7.36 (s, 1H), 7.56 (d, 2H, J = 8.8 Hz). GC/MS m/z 436 (M+ + 1, 20), 435 (M+, 100), 281 (70), 212 (57), 167 (34). Anal. (C24H29N5O3·HCl·H2O) C, H, N.

2-{2-[4-[2-(4-Methoxyphenyl)phenylpiperazin-1-yl]butyl}-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione (8c)

Eluted with CHCl3/MeOH, 95:5. Pale yellow oil, 30% yield. 1H NMR (CDCl3): δ 1.47 (m, 2H), 1.71–1.80 (m, 2H), 2.34 (app t, 6H), 2.85 (app t, 4H), 3.33 (s, 3H), 3.98 (t, 2H, J = 7.0 Hz), 6.91–6.95 (m, 2H), 7.00–7.07 (m, 2H), 7.29–7.24 (m, 2H), 7.37 (s, 1H), 7.55–7.59 (m, 2H). 13C NMR (500 MHz, CDCl3): δ 158.7; 155.9; 148.9; 147.7; 134.9; 134.3; 132.7; 131.5; 129.9; 128.36; 124.3; 118.9; 113.8; 124.2; 118.7; 113.8; 55.3; 52.4; 50.5; 47.7; 27.1. ESI-MS m/z 472 (M + Na)+. ESI-MS/MS m/z 323 (100). Anal. (C25H31N5O3·HCl) C, H, N.

2-[4-[4-(2-Acetylphenyl)piperazin-1-yl]butyl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione (9)

Eluted with CHCl3/MeOH, 98:2. Yellow oil, 20% yield. 1H NMR (CDCl3): δ 1.57 (m, 2H), 1.81 (m, 2H), 2.44 (t, 2H, J = 7.6 Hz), 2.60 (br s, 4H), 2.65 (s, 3H), 3.02 (app. t, 4H), 3.35 (s, 3H), 4.02 (t, 2H, J = 7.1 Hz), 7.04–7.08 (m, 2H), 7.39–7.42 (m, 3H). GC/MS m/z 386 (M+ + 1, 10), 385 (M+, 30), 237 (90), 207 (100), 161 (95). Anal. (C20H27N5O3·2HCl) C, H, N.

3-{2-[4-[2-(4-Methoxyphenyl)phenyl]piperazin-1-yl]ethyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (11a)

Eluted with CHCl3/MeOH, 98:2. Brown solid, 60% yield. 1H NMR (CDCl3): δ 1.84–1.89 (m, 2H), 1.92–1.97 (m, 2H), 2.27 (s, 3H), 2.45–2.50 (m, 6H), 2.69–2.72 (br t, 2H), 2.85 (t, 2H, J = 6.8 Hz), 2.89 (br s, 4H), 3.85 (s, 3H), 3.91 (t, 2H, J = 6.1 Hz), 6.90–6.93 (m, 2H), 7.03–7.06 (m, 2H), 7.21 (dd, 1H, J = 1.5 and 7.3 Hz), 7.25 (td, 1H, J = 1.5 and 7.8 Hz), 7.55–7.58 (m, 2H). GC/MS m/z 458 (M+, 2), 281 (100). Anal. (C28H34N4O2·2HCl) C, H, N.

3-{3-[4-[2-(4-Methoxyphenyl)phenyl]piperazin-1-yl]propyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (11b)

Eluted with CHCl3/EtOAc, 1:1. Brown oil, 60% yield. 1H NMR (CDCl3): δ 1.51–1.53 (m, 2H), 1.84–1.89 (m, 2H), 1.93–1.98 (m, 2H), 2.27 (s, 3H), 2.45–2.50 (m, 6H), 2.69–2.73 (br t, 2H), 2.85 (t, 2H, J = 6.8 Hz), 2.85 (br s, 4H), 3.85 (s, 3H), 3.91 (t, 2H, J = 6.1 Hz), 6.90–6.93 (m, 2H), 7.03–7.06 (m, 2H), 7.21 (dd, 1H, J = 1.5 and 7.3 Hz), 7.25 (td, 1H, J = 1.5 and 7.8 Hz), 7.55–7.58 (m, 2H). 13C NMR (500 MHz, CDCl3): δ 162.6; 158.4; 155.6; 134.5; 133.5; 131.3; 129.8; 129.7; 127.9; 122.6; 118.2; 113.5; 58.13; 55.2; 53.2; 50.6; 42.7; 31.4; 24.1; 22.0; 21.21; 19.25. GC/MS m/z 473 (M+ + 1, 2), 472 (M+, 9), 281 (42), 234 (100), 205 (51). Anal. (C29H36N4O2·2HCl·H2O) C, H, N.

7-[2-[4-[2-(4-Methoxyphenyl)phenyl]piperazin-1-yl]ethoxy]-4-methyl-2H-chromen-2-one (20a)

Eluted with CHCl3/EtOAc, 1:1. Pale yellow oil, 71% yield. 1H NMR (CDCl3): δ 2.39 (s, 3H), 2.54 (br s, 4H), 2.84 (br t, 2H), 2.91 (br s, 4H), 3.85 (s, 3H), 4.15 (br t, 2H), 6.13 (d, 1H, J = 1.5 Hz), 6.80 (d, 1H, J = 2.5 Hz), 6.86 (dd, 1H, J = 2.5 and 8.8 Hz), 6.92–6.95 (m, 2H), 7.03–7.06 (m, 2H), 7.22 (dd, 1H, J = 1.5 and 7.3 Hz), 7.24–7.27 (m, 1H), 7.48 (d, 1H, J = 8.8 Hz), 7.56–7.59 (m, 2H). ESI-MS m/z 493 (M + Na)+. ESI-MS/MS m/z 493 (89), 295 (100). Anal. (C29H30N2O4·HCl) C, H, N.

6-[3-[4-[2-(4-Methoxyphenyl)phenyl]piperazin-1-yl]propoxy]-4-methyl-2H-chromen-2-one (20b)

Eluted with CH2Cl2/EtOAc, 1:1. Transparent oil, 15% yield. 1H NMR (CDCl3): δ 1.94–1.99 (m, 2H), 2.39 (br s, 7H), 2.50–2.52 (br t, 2H), 2.86 (br s, 4H), 3.85 (s, 3H), 4.03–4.07 (br t, 2H), 6.12 (s, 1H), 6.80–6.85 (m, 2H), 6.91–6.94 (m, 2H), 7.01–7.27 (m, 2H), 7.20–7.27 (m, 3H), 7.47 (d, 1H, J = 8.2 Hz), 7.56–7.59 (m, 2H). 13C NMR (500 MHz, CDCl3): δ 162.2; 161.5; 158.5; 155.4; 152.7; 134.7; 133.7; 131.5; 130.0; 128.1; 125.6; 122.8; 118.3; 113.7; 112.7; 112.0; 101.6; 66.9; 55.4; 55.1; 53.6; 50.9; 26.6; 18.8. ESI-MS m/z 507 (M+Na)+. ESI-MS/MS m/z 507 (100), 309 (63). Anal. (C30H32N2O4·HCl) C, H, N.

7-[4-[4-[2-(4-Methoxyphenyl)phenyl]piperazin-1-yl]butoxy]-4-methyl-2H-1-chromen-2-one (20c)

Eluted with CHCl3/MeOH, 98:2. Pale yellow oil, 36% yield. 1H NMR (CDCl3): δ 1.65–1.72 (m, 2H), 1.85–1.94 (m, 2H,) 2.38–2.43 (m + d, 9H, J = 1.1 Hz), 2.85 (app t, 4H), 3.86 (s, 3H), 4.14 (t, 2H, J = 6.0 Hz), 6.17 (d, 1H, J = 1.1 Hz), 6.87–6.95 (m, 3H), 7.00–7.08 (m, 2H), 7.20–7.23 (m, 3H), 7.43 (d, 1H, J = 8.8 Hz), 7.55–7.60 (m, 2H). ESI-MS m/z 497 (M + H)+. ESI-MS/MS m/z 497 (69), 335 (100). Anal. (C31H34N2O4·HCl·H2O) C, H, N.

6-[2-[4-[2-(4-Methoxyphenyl)phenyl]piperazin-1-yl]ethoxy]-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (26a)

Eluted with CHCl3/MeOH, 98:2. Transparent oil, 38% yield. 1H NMR (CDCl3): δ 1.55 (d, 3H, J = 6.9 Hz), 2.53 (br s, 4H), 2.79–2.81 (m, 2H), 2.89 (br t, 4 H), 3.86 (s, 3H), 4.04 (app t, 2H), 4.57 (q, 1H, J = 6.9 Hz), 6.36 (d, 1H, J = 2.9 Hz), 6.49 (dd, 1H, J = 2.9 and 8.8 Hz), 6.87 (d, 1H, J = 8.8 Hz), 6.92–6.95 (m, 2H), 7.01–7.07 (m, 2H), 7.21–7.27 (m, 2H), 7.55–7.58 (m, 2H), 8.27 (s, 1H, D2O exchanged). ESI-MS m/z 474 (M + H)+. ESI-MS/MS m/z 474 (76), 226 (100). Anal. (C28H31N3O4·2HCl) C, H, N.

6-[3-[4-[2-(4-Methoxyphenyl)phenyl]piperazin-1-yl]propoxy]-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (26b)

Eluted with CHCl3/MeOH, 98:2. Transparent oil, 17% yield. 1H NMR (CDCl3): δ 1.55 (d, 3H, J = 2.5 Hz), 1.92–1.95 (m, 2H), 2.43 (br s, 4H), 2.51 (app t, 2H), 2.88 (br s, 4 H), 3.85 (s, 3H), 3.93 (t, 2H, J = 6.4 Hz), 4.57 (q, 1H, J = 6.9 Hz), 6.34 (d, 1H, J = 2.5 Hz), 6.49 (dd, 1H, J = 2.5 and 8.8 Hz), 6.86 (d, 1H, J = 8.8 Hz), 6.92–6.94 (m, 2H), 7.01–7.07 (m, 2H), 7.21–7.27 (m, 2H), 7.55–7.56 (m, 2H), 8.13 (s, 1H, D2O exchanged). GC/MS m/z 488 (M+ + 1, 5), 487 (M+, 20), 281 (30), 194 (100), 165 (33), 91 (34). Anal. (C29H33N3O4·2HCl) C, H, N.

2-[2-[4-[2-(4-Methoxyphenyl)phenyl]piperazin-1-yl]ethyl]tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione (33a)

Eluted with CHCl3/EtOAc, 1:1. Transparent oil, 74% yield. 1H NMR (CDCl3): δ 1.64–1.74 (m, 1H), 1.98–2.07 (m, 2H), 2.17–2.25 (m, 1H), 2.40 (br s, 4H), 2.49–2.58 (m, 2H), 2.78 (br s, 4H), 3.19–3.24 (m, 1H), 3.53–3.59 (m, 2H), 3.64–3.69 (m, 1H), 3.85 (s, 3H), 4.05 (t, 1H, J = 8.3 Hz), 6.90–6.93 (m, 2H), 7.04 (td, 1H, J = 1.0 and 7.4 Hz), 7.19–7.25 (m, 2H), 7.54–7.56 (m, 2H). 13C NMR (500 MHz, CDCl3): δ 174.2; 161.1; 158.5; 150.3; 134.7; 133.7; 131.4; 129.9; 127.9; 122.7; 118.3; 63.4; 55.7; 54.9; 53.6; 53.2; 51.1; 45.9; 36.2; 27.8; 27.0. GC/MS m/z 435 (M+ + 1, 3), 434 (M+, 13), 281 (100). Anal. (C25H30N4O3·HCl·H2O) C, H, N.

2-[3-[4-[2-(4-Methoxyphenyl)phenyl]piperazin-1-yl]propyl]tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione (33b)

Eluted with CHCl3/EtOAc, 1:1. Brown oil, 43% yield. 1H NMR (CDCl3): δ 1.64–1.71 (m, 2H), 1.72–1.82 (m, 2H), 2.02–2.11 (m, 2H), 2.18–2.28 (m, 2H), 2.34–2.38 (m, 5H), 2.85 (br s, 4H), 3.19–3.27 (m, 1H), 3.48–3.52 (m, 2H), 3.62–3.70 (m, 2H), 3.85 (s, 3H), 4.02–4.07 (m, 1H), 6.92 (d, 2H, J = 8.88 Hz), 6.99–7.07 (m, 2H), 7.19–7.27 (m, 2H), 7.55 (d, 2H, J = 8.8 Hz). GC/MS m/z 449 (M+ + 1, 20), 448 (M+, 80), 281 (100), 210 (50), 70 (31). Anal. (C26H32N4O3·HCl·H2O) C, H, N.

General Procedure for the Preparation of Compounds 29 and 30

A mixture of 1-[2-(4-methoxyphenyl)phenyl]piperazine or 1(2-acetylphenyl)piperazine (1.2 mmol) and the oxirane 28 (1.0 mmol) in ethanol (20 mL) was refluxed for 5 h. After it was cooled, the solvent was removed in vacuo, and the crude residue was chromatographed as detailed below to give desired pure compound.

6-{(2R)-2-Hydroxy-3-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]propoxy}-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (29)

Eluted with CHCl3/AcOEt, 1:1. White semisolid, 30% yield. 1H NMR (CDCl3): δ 1.62 (br s, 1H, D2O exchanged), 1.47 (d, 3H, J = 6.8 Hz), 2.30–2.32 (m, 2H,), 2.39–2.45 (m, 2H), 2.48–2.54 (m, 2H), 2.79–2.83 (m, 4H), 3.78 (s, 3H), 3.82 (d, 2H, J = 4.9 Hz), 3.94–3.97 (m, 1H), 4.49 (q, 1H, J = 6.8 Hz), 6.79 (d, 1H, J = 8.8 Hz), 6.84–6.87 (m, 2H), 6.94 (dd, 1H, J = 1.1 and 8.3 Hz), 6.99 (td, 1H, J = 1.5 and 7.3 Hz), 7.14–7.20 (m, 4H), 7.48–7.51 (m, 2H), 8.35 (br, 1H, D2O exchanged). 13C NMR (500 MHz, CDCl3): δ 168.0; 167.9; 158.7; 153.4; 147.8; 137.6; 137.5; 134.9; 132.6; 131.5; 129.8; 128.2; 127.5; 124.2; 118.7; 117.2; 114.0; 109.9; 102.6; 73.2; 70.4; 64.6; 61.0; 55.4; 54.7; 53.4; 47.8; 47.7; 16.0. ESI-MS m/z 526 (M+Na)+. ESI-MS/MS m/z 526 (100), 347 (11). Anal. (C29H33N3O5·HCl) C, H, N.

6-[3-[4-(2-Acetylphenyl)piperazin-1-yl]-(2R)-2-hydroxypropoxy]-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (30)

Eluted with CHCl3/MeOH, 95:5. Brown oil, 54% yield. 1H NMR (CDCl3): δ 1.50 (d, 3H, J = 6.9 Hz), 1.81 (br s, 1H, D2O exchanged), 2.56–2.64 (m, 4H), 2.65 (s, 3H), 2.78–2.83 (m, 2H), 3.05 (br, 4 H), 3.94–3.96 (m, 2H), 4.09–4.11 (m, 1H), 4.57 (q, 1H, 6.9 Hz), 6.44 (s, 1H), 6.52 (dd, 1H, J = 2.4 and 8.8 Hz), 6.87 (d, 1H, J = 8.8 Hz), 7.05–7.08 (m, 2H), 7.39–7.42 (m, 2H), 8.49 (br s, 1H, D2O exchanged). ESI-MS m/z 462 (M + Na)+. ESI-MS/MS m/z 462 (100). Anal. (C24H29N3O5·2HCl) C, H, N.

Radioligand Binding Assays

Materials

Cell culture reagents were purchased from EuroClone (Milan, Italy). G418 (Geneticin), 5-HT, and NAN-190 were obtained from Sigma-Aldrich (Milano, Italy). 5-CT was purchased from Tocris Bioscience (Bristol, UK). [3H]-5-CT and [3H]-8-OH-DPAT were obtained from PerkinElmer Life and Analytical Sciences (Boston, MA, USA). MultiScreen plates with Glass fiber filters was purchased from Merck Millipore (Billerica, MA, USA). pcDNA3.1(+) vector containing the target 5-HT1A DNA sequence was purchased from cDNA Resource Center (Bloomsberg, PA, USA), and FuGENE HD Transfection Reagent was obtained from Promega (Madison, Wisconsin, USA).

Cell Culture

HEK-293 cell line was grown in DMEM high glucose supplemented with 10% fetal bovine serum, 2 mM glutamine, 100 U/mL penicillin, and 100 μg/mL streptomycin, in a humidified incubator at 37 °C with a 5% CO2 atmosphere. HEK-293-5-HT7A and HEK-293-5-HT1A transfected cell lines were grown in DMEM high glucose supplemented with 10% fetal bovine serum, 2 mM glutamine, 100 U/mL penicillin, 100 μg/mL streptomycin, and 0.8 μg/mL G418, in a humidified incubator at 37 °C with a 5% CO2 atmosphere.

Radioligand Binding at Human Cloned 5-HT7Rs

5-HT7R binding was carried out as previously reported. (57) The experiment was performed in MultiScreen plates (Merck Millipore) with Glass fiber filters (GF/C), presoaked in 0.3% PEI for 20 min. After this time, 130 μg of HEK-293-5-HT7A membranes, 1 nM [3H]-5-CT, and the test compounds were suspended in 0.25 mL of incubation buffer (50 mM Tris–HCl, pH 7.4, 4 mM MgCl2, 0.1% ascorbic acid, 10 μM pargyline hydrochloride). The samples were incubated for 60 min at 37 °C. The incubation was stopped by rapid filtration, and the filters were washed with 3 × 0.25 mL of ice-cold buffer (50 mM TRIS-HCl, pH 7.4). Nonspecific binding was determined in the presence of 10 μM 5-CT. Approximately 90% of specific binding was determined under these conditions. Concentrations required to inhibit 50% of radioligand specific binding (IC50) were determined by using six to nine different concentrations of the drug studied in two or three experiments with samples in duplicate. Apparent inhibition constants (Ki) values were determined by nonlinear curve fitting, using the Prism, version 5.0, GraphPad software.

Radioligand Binding at Human Cloned 5-HT1AR

5-HT1AR binding was carried out as already reported. (57) The experiment was performed in MultiScreen plates (Merck Millipore) with Glass fiber filters (GF/C), presoaked in 0.3% PEI for 20 min. After this time, 100 μg of HEK-293-5-HT1A membranes, 1.5 nM [3H]-8-OH-DPAT, and the test compound were suspended in a 0.25 mL of incubation buffer (50 mM Tris–HCl pH 7.4, 4 mM MgCl2, 0.1% ascorbic acid, 0.1 nM EDTA, 10 μM pargyline hydrochloride). The samples were incubated for 60 min at 25 °C. The incubation was stopped by rapid filtration, and the filters were washed with 3 × 0.25 mL of ice-cold buffer (50 mM TRIS-HCl, pH 7.4). Nonspecific binding was determined in the presence of 10 μM NAN-190. Approximately 90% of specific binding was determined under these conditions. Concentrations required to inhibit 50% of radioligand specific binding (IC50) were determined by using six to nine different concentrations of the test compound in two or three experiments with samples in duplicate. Apparent inhibition constants (Ki) values were determined by nonlinear curve fitting, using the Prism, version 5.0, GraphPad software.

Radioligand Binding at Human Cloned Dopamine D2 and Serotonin 5-HT2A Receptors

The affinity of the compounds for dopamine D2 and serotonin 5-HT2A receptors was evaluated in membrane preparations from CHO-K1 cells stably expressing the human cloned D2S receptor or the human cloned 5-HT2A receptor, following previously described procedures. (58) Competition binding experiments were performed using [3H]spiperone (0.2 nM; D2 receptor) or [3H]ketanserin (1 nM; 5-HT2AR) as radioligands. Nonspecific binding was assessed in the presence of 10 μM sulpiride (D2 receptor) or 1 μM methysergide (5-HT2AR). Haloperidol (D2 receptor) and risperidone (5-HT2AR) were included in the assays as reference compounds. Competition binding curves constructed with 6 different concentrations of the compounds were fitted to a one-site competition model using Prism 6 software (GraphPad, San Diego, CA, USA), and equilibrium dissociation constant (Ki) of the compounds was calculated according to the Cheng–Prusoff equation.

Analysis of the cAMP Response Using FRET-Based Biosensor CEPAC

Mouse neuroblastoma N1E115 cells (American Type Culture Collection, Manassas, USA) were seeded onto 18 mm glass coverslips and grown in DMEM containing 10% fetal bovine serum and 1% penicillin/streptomycin at 37 °C in a humidified atmosphere with 5% CO2. Expression of the cAMP-biosensor CEPAC, 5-HT7R, or 5-HT1AR was ensured by transfection (plasmid DNA to biosensor and receptor ratio of 7:3) using Lipofectamine 2000 (Life Technologies). One day after transfection, changes in cAMP levels upon perfusion with 10 μM 8c, 20b, 29, LP-211, or 5-CT 5-HT7R in Tyrode’s buffer (150 mM NaCl; 5 mM KCl; 1 mM MgCl2; 2 mM CaCl2; 10 mM HEPES; pH 7.4; adjusted osmolarity) were monitored in real-time under a Zeiss LSM 780 confocal laser-scanning microscope. A 61 cycle time series with a 10 s interval was recorded in online fingerprinting mode of the ZEN acquisition software with the following settings: image dimension = 1024 pixels × 1024 pixels, resolution = 0.346 μm × 0.346 μm, excitation = 440 nm diode and 561 nm DPSS laser lines, filters = MBS 445, MBS 458/561, objective = C-Apochromat 40×/1.2W Corr. Corresponding reference spectra for the online fingerprinting mode were obtained from separate measurements with a single fluorophore transfection. The semiautomatic biosensor data analysis relied on custom-written MATLAB scripts comprising data import, preprocessing, shift correction in the xy-plane for each time point, the exclusion of saturated pixels from evaluation, background correction, and faint data blurring with a kernel size of 0.5 according to Pawley. (59) The pixel-based ratio was calculated for selected regions of interest (ROIs) for evaluation. Traces were normalized according to their mean ratio before stimulation.

Functional Assays at 5-HT2A Receptor

The efficacy of compounds 8c, 20b, and 29 at 5-HT2A receptor was investigated in assays of inositol phosphate (IP) production in the CHO-K1 cell line stably expressing the cloned human 5-HT2A receptor employed in radioligand binding assays. Cellular IP levels were quantified by using the homogeneous time-resolved fluorescence (HTRF)-based inositol monophosphate kit IP-One Gq kit (Cisbio, Bioassays, Codolet, France) following the manufacturer protocol. Cells were seeded in 96-well plates in culture medium DMEM (Gibco, ThermoFisher Scientific, Madrid, Spain) supplemented with 10% (v/v) dialyzed fetal bovine serum (Sigma-Aldrich, Madrid, Spain), 100 U/mL penicillin/0.1 mg/mL streptomycin (Sigma-Aldrich, Madrid, Spain), and 2 mM l-glutamine (Sigma-Aldrich, Madrid, Spain)) and maintained during 24 h at 37 °C in a 5% CO2 humidified atmosphere. Prior to the assay, cell supernatant was removed and for assessment of possible agonist effect, and cells were incubated with the compounds (0.1 nM–100 μM) or 5-HT (0.1 nM–100 μM) as control agonist in stimulation buffer for 20 min at 37 °C. After this time, IP levels were quantified. For assessment of possible antagonist effect, the compounds (0.1 nM–100 μM) were added to the cells 10 min prior to the addition of 1 μM 5-HT, and assays were subsequently carried out as described above. Risperidone (0.1 nM–100 μM) was used as control antagonist in these assays. In all cases, basal IP levels were determined in control wells in the absence of compound and agonist. Antagonist concentration–response curves were fitted to a sigmoidal dose–response (inhibition) model (Hill slope (nH) = 1, with best fit in comparison to sigmoidal dose–response (variable slope) model, P < 0.05, extra sum-of-squares F test) using Prism 6 software (GraphPad, San Diego, CA) to retrieve pIC50 (−log IC50) values.

Stability Assays in Rat Liver Microsomes

Test compounds were preincubated at 37 °C with rat liver microsomes (Tebu-Bio, Milan, Italy) (1.0 mg/mL microsomal protein) at 10 μM final concentration in 100 mM potassium phosphate buffer (pH 7.4) for 10 min. Metabolic reactions were initiated by the addition of the NADPH regenerating system (containing 10 mM NADP, 50 mM glucose-6-phosphate, and 10 unit/mL glucose-6-phosphate dehydrogenase, final glucose-6-phosphate dehydrogenase concentration, 1 unit/mL). Aliquots were removed at specific time end points and immediately mixed with an equal volume of cold acetonitrile containing the internal standard. To assess in vitro in vitro half-life (t1/2) the aliquots were removed at 0, 5, 15, 30, 60, and 120 min. Test compound incubated with microsomes without NADPH regenerating system was included. Quenched samples were centrifuged at 4500 rpm for 15 min, and the supernatants were injected for quantification analysis. Samples (100 μL) were analyzed by using an Agilent 1260 Infinity Binary LC System equipped with a diode array detector (Open Lab software was used to analyze the chromatographic data) and a Phenomenex Gemini C-18 column (250 mm × 4.6 mm, 5 μm particle size). The samples were eluted using CH3CN/20 mM ammonium formate pH 5.5 (70:30, v/v) as eluent (1 mL/min). Concentrations were quantified by measuring the area under the peak. The percentage of the parent compound remaining after a 30 min incubation has been calculated according to the equation
where Cparent is ligand concentration after incubation with microsome fraction and NADPH regenerating system and Ccontrol is ligand concentration after incubation with microsome fraction only.
The in vitro half-life (t1/2) was calculated using the expression t1/2 = 0.693/b, where b is the slope found in the linear fit of the natural logarithm of the fraction remaining of the parent compound vs incubation time. (41) In vitro half-life was then used to calculate the intrinsic plasma clearance (CLint) according to the following equation:
Internal positive controls were aripiprazole (Cint = 6.93 mL/mg/min, t1/2 = 100 min) and LP-211 (Cint= 45.9 mL/mg/min, t1/2 = 45.9 min).

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acschemneuro.0c00647.

  • General procedures and spectroscopic data of intermediates 7a,b, 12, 13, 15, 16, 19a–c, 22, 23, 24, 25a,b, 26b, 28, and 32a,b; formula, molecular weight, and monoisotopic mass of the synthesized compounds; elemental analysis of target compounds; off-target affinities of selected target compounds; and 1H NMR spectra of target compounds 8a–c, 9, 14a,b, 20a–c, 26a–c, 33a,b, 29, and 30 (PDF)

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Author Information

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  • Corresponding Authors
  • Authors
    • Mauro Niso - Dipartimento di Farmacia−Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, via Orabona, 4, 70125 Bari, Italy
    • Margherita Mastromarino - Dipartimento di Farmacia−Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, via Orabona, 4, 70125 Bari, Italy
    • Andrea Garcia Silva - Center for Research in Molecular Medicine and Chronic Diseases (CIMUS). Universidade de Santiago de Compostela. Avda. de Barcelona, s/n, 15782 Santiago de Compostela, Spain
    • Cibell Resch - Cellular Neurophysiology, Hannover Medical School, 30625 Hannover, Germany
    • Andre Zeug - Cellular Neurophysiology, Hannover Medical School, 30625 Hannover, Germany
    • María I. Loza - Center for Research in Molecular Medicine and Chronic Diseases (CIMUS). Universidade de Santiago de Compostela. Avda. de Barcelona, s/n, 15782 Santiago de Compostela, Spain
    • Marián Castro - Center for Research in Molecular Medicine and Chronic Diseases (CIMUS). Universidade de Santiago de Compostela. Avda. de Barcelona, s/n, 15782 Santiago de Compostela, Spain
    • Evgeni Ponimaskin - Cellular Neurophysiology, Hannover Medical School, 30625 Hannover, Germany
  • Funding

    The present work was partially supported by Telethon Foundation Grant GGP13145 (M.L.) and by German Research Foundation (DFG) (grant number PO732 to E.P. and grant number ZE994/2 to A.Z.). A.G.S., M.I.L., and M.C. acknowledge support from the Spanish Ministry of Economy and Competitiveness (MINECO) (grant number SAF2014-57138-C2–1-R), Xunta de Galicia (Centro singular de investigación de Galicia accreditation 2019–2022, grant number ED431G 2019/02), and the European Union (European Regional Development Fund - ERDF). COST Action CA 18133 “European Research Network on Signal Transduction – ERNEST” is gratefully acknowledged. Funding for open access charge: COST Action CA18133 (ERNEST).

  • Notes
    The authors declare no competing financial interest.

Abbreviations

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5-HT

serotonin

5-HT1AR

serotonin 1A receptor

5-HT2AR

serotonin 2A receptor

5-HT7R

serotonin 7 receptor

8-OH-DPAT

8-hydroxy-2-dipropylaminotetralin

(+)-5-FTP

(+)-5-(2′-fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahidronaphthalen-2-amine

ADME

absorption, distribution, metabolism, and excretion

ASD

autism spectrum disorder

cAMP

cyclic adenosine monophosphate

CLint app

apparent intrinsic clearance

CNS

central nervous system

FRET

fluorescence resonance energy transfer

SAR

structure–activity relationship

SSRI

selective serotonin reuptake inhibitor

References

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    Serotonin neuron abnormalities in the BTBR mouse model of autism
    Guo Yue-Ping; Guo Yue-Ping; Commons Kathryn G
    Autism research : official journal of the International Society for Autism Research (2017), 10 (1), 66-77 ISSN:.
    The inbred mouse strain BTBR T(+) Itpr3(tf) /J (BTBR) is studied as a model of idiopathic autism because they are less social and more resistant to change than other strains. Forebrain serotonin receptors and the response to serotonin drugs are altered in BTBR mice, yet it remains unknown if serotonin neurons themselves are abnormal. In this study, we found that serotonin tissue content and the density of serotonin axons is reduced in the hippocampus of BTBR mice in comparison to C57BL/6J (C57) mice. This was accompanied by possible compensatory changes in serotonin neurons that were most pronounced in regions known to provide innervation to the hippocampus: the caudal dorsal raphe (B6) and the median raphe. These changes included increased numbers of serotonin neurons and hyperactivation of Fos expression. Metrics of serotonin neurons in the rostral 2/3 of the dorsal raphe and serotonin content of the prefrontal cortex were less impacted. Thus, serotonin neurons exhibit region-dependent abnormalities in the BTBR mouse that may contribute to their altered behavioral profile. Autism Res 2017, 10: 66-77. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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  10. 10
    Brandenburg, C. and Blatt, G. J. (2019) Differential serotonin transporter (5-HTT) and 5-HT2 receptor density in limbic and neocortical areas of adults and children with autism spectrum disorders: implications for selective serotonin reuptake inhibitor efficacy. J. Neurochem. 151, 642– 655,  DOI: 10.1111/jnc.14832
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    10
    Differential serotonin transporter (5-HTT) and 5-HT2 receptor density in limbic and neocortical areas of adults and children with autism spectrum disorders: implications for selective serotonin reuptake inhibitor efficacy
    Brandenburg, Cheryl; Blatt, Gene J.
    Journal of Neurochemistry (2019), 151 (5), 642-655CODEN: JONRA9; ISSN:0022-3042. (Wiley-Blackwell)
    As selective serotonin reuptake inhibitors (SSRIs) are among the most commonly prescribed medications in autism, we aimed to det. whether targets for SSRIs are differentially affected in three cortical areas in children and adults with autism compared to neurotypical individuals. Utilizing a large cohort of postmortem brain tissue (n = 14-19 per group), satn. ligand binding assays were conducted on sections from the anterior cingulate cortex (ACC), posterior cingulate cortex, and fusiform gyrus (FG). Specific binding to the 5-HT transporter (5-HTT) as well as to 5-HT2 and 1A receptors (5-HT2, 5-HT1A) was quantified in superficial and deep layers of each region using the ligands [3H]-citalopram (5-HTT), [3H]-ketanserin (5-HT2), and [3H]-8-OH-DPAT (5-HT1A). A Welch's t-test was utilized to compare receptor densities (Bmax), revealing a statistically significant decrease in 5-HTT within the ACC of the entire autism cohort. There was also a decrease in 5-HT2 receptor d. in the ACC in the adult cohort, but not in child postmortem autism cases as compared to controls. Comparing linear regression lines of Bmax values plotted against age, shows a significantly lower intercept for 5-HTT in autism (p = 0.025). 5-HT2 d. increases with age in control cases, whereas in autism there is a decrease with age and significantly different slopes between regression lines (p = 0.032). This suggests a deficit in 5-HTT within the ACC in individuals with autism, while decreases in 5-HT2 d. are age-dependent. There were no differences in receptor densities in the posterior cingulate cortex or FG in autism and no differences in ligand affinity (KD) across all regions and ligands examd.
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  11. 11
    Chugani, D. C., Chugani, H. T., Wiznitzer, M., Parikh, S., Evans, P. A., Hansen, R. L., Nass, R., Janisse, J. J., Dixon-Thomas, P., Behen, M. (2016) Efficacy of Low-Dose Buspirone for Restricted and Repetitive Behavior in Young Children with Autism Spectrum Disorder: A Randomized Trial. J. Pediatr. 170, 45– 53,  DOI: 10.1016/j.jpeds.2015.11.033
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    11
    Efficacy of Low-Dose Buspirone for Restricted and Repetitive Behavior in Young Children with Autism Spectrum Disorder: A Randomized Trial
    Chugani, Diane C.; Chugani, Harry T.; Wiznitzer, Max; Parikh, Sumit; Evans, Patricia A.; Hansen, Robin L.; Nass, Ruth; Janisse, James J.; Dixon-Thomas, Pamela; Behen, Michael; Rothermel, Robert; Parker, Jacqueline S.; Kumar, Ajay; Muzik, Otto; Edwards, David J.; Hirtz, Deborah
    Journal of Pediatrics (New York, NY, United States) (2016), 170 (), 45-53.e4CODEN: JOPDAB; ISSN:0022-3476. (Elsevier)
    To det. safety and efficacy of the 5HT1A serotonin partial agonist buspirone on core autism and assocd. features in children with autism spectrum disorder (ASD). Children 2-6 years of age with ASD (N = 166) were randomized to receive placebo or 2.5 or 5.0 mg of buspirone twice daily. The primary objective was to evaluate the effects of 24 wk of buspirone on the Autism Diagnostic Observation Schedule (ADOS) Composite Total Score. Secondary objectives included evaluating the effects of buspirone on social competence, repetitive behaviors, language, sensory dysfunction, and anxiety and to assess side effects. Positron emission tomog. measures of tryptophan metab. and blood serotonin concns. were assessed as predictors of buspirone efficacy. There was no difference in the ADOS Composite Total Score between baseline and 24 wk among the 3 treatment groups (P = .400); however, the ADOS Restricted and Repetitive Behavior score showed a time-by-treatment effect (P = .006); the 2.5-mg buspirone group showed significant improvement (P = .003), whereas placebo and 5.0-mg buspirone groups showed no change. Children in the 2.5-mg buspirone group were more likely to improve if they had fewer foci of increased brain tryptophan metab. on positron emission tomog. (P = .018) or if they showed normal levels of blood serotonin (P = .044). Adverse events did not differ significantly among treatment groups. Treatment with 2.5 mg of buspirone in young children with ASD might be a useful adjunct therapy to target restrictive and repetitive behaviors in conjunction with behavioral interventions. ClinicalTrials.gov: NCT00873509.
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  12. 12
    Gould, G. G., Hensler, J. G., Burke, T. F., Benno, R. H., Onaivi, E. S., and Daws, L. C. (2011) Density and function of central serotonin (5-HT) transporters, 5-HT1A and 5-HT2A receptors, and effects of their targeting on BTBR T+tf/J mouse social behavior. J. Neurochem. 116, 291– 303,  DOI: 10.1111/j.1471-4159.2010.07104.x
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    12
    Density and function of central serotonin (5-HT) transporters, 5-HT1A and 5-HT2A receptors, and effects of their targeting on BTBR T+tf/J mouse social behavior
    Gould, Georgianna G.; Hensler, Julie G.; Burke, Teresa F.; Benno, Robert H.; Onaivi, Emmanuel S.; Daws, Lynette C.
    Journal of Neurochemistry (2011), 116 (2), 291-303CODEN: JONRA9; ISSN:0022-3042. (Wiley-Blackwell)
    BTBR mice are potentially useful tools for autism research because their behavior parallels core social interaction impairments and restricted-repetitive behaviors. Altered regulation of central serotonin (5-HT) neurotransmission may underlie such behavioral deficits. To test this, we compared 5-HT transporter (SERT), 5-HT1A and 5-HT2A receptor densities among BTBR and C57 strains. Autoradiog. [3H] cyanoimipramine (1 nM) binding to SERT was 20-30% lower throughout the adult BTBR brain as compared to C57BL/10J mice. In hippocampal membrane homogenates, [3H] citalopram maximal binding (Bmax) to SERT was 95 fmol/mg protein in BTBR and 171 fmol/mg protein in C57BL/6J mice, and the BTBR dissocn. const. (KD) was 2.0 nM vs. 1.1 in C57BL/6J mice. Hippocampal 5-HT1A and 5-HT2A receptor binding was similar among strains. However, 8-OH-DPAT-stimulated [35S] GTPγS binding in the BTBR hippocampal CA1 region was 28% higher, indicating elevated 5-HT1A capacity to activate G-proteins. In BTBR mice, the SERT blocker, fluoxetine (10 mg/kg) and the 5-HT1A receptor partial-agonist, buspirone (2 mg/kg) enhanced social interactions. The D2/5-HT2 receptor antagonist, risperidone (0.1 mg/kg) reduced marble burying, but failed to improve sociability. Overall, altered SERT and/or 5-HT1A functionality in hippocampus could contribute to the relatively low sociability of BTBR mice.
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  13. 13
    Wang, C.-C., Lin, H.-C., Chan, Y.-H., Gean, P.-W., Yang, Y. K., and Chen, P. S. (2013) 5-HT1A-receptor agonist modified amygdala activity and amygdala-associated social behavior in a valproate-induced rat autism model. Int. J. Neuropsychopharmacol. 16, 2027– 2039,  DOI: 10.1017/S1461145713000473
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    13
    5-HT1A-receptor agonist modified amygdala activity and amygdala-associated social behavior in a valproate-induced rat autism model
    Wang, Chao-Chuan; Lin, Hui-Ching; Chan, Yun-Han; Gean, Po-Wu; Yang, Yen Kung; Chen, Po See
    International Journal of Neuropsychopharmacology (2013), 16 (9), 2027-2039CODEN: IJNUFB; ISSN:1461-1457. (Cambridge University Press)
    Accumulating evidence suggests that dysfunction of the amygdala is related to abnormal fear processing, anxiety, and social behaviors noted in autistic spectrum disorders (ASDs). In addn., studies have shown that disrupted brain serotonin homeostasis is linked to ASD. With a valproate (VPA)-induced rat ASD model, we investigated the possible role of amygdala serotonin homeostasis in autistic phenotypes and further explored the underlying mechanism. We first discovered that the distribution of tryptophan hydroxylase immunoreactivity in the caudal raphe system was modulated on postnatal day (PD) 28 of the VPA-exposed offspring. Then, we found a significantly higher serotonin transporter availability in the amygdala of the VPA-exposed offspring on PD 56 by using single photon emission computed tomog. and computed tomog. co-registration following injection of 123I-labeled 2-((2-(dimethylamino)methyl)phenyl)thio-5-iodophenylamine(123I[ADAM]). Furthermore, treatment with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, increased social interaction and improved fear memory extinction in the VPA-exposed offspring. 8-OH-DPAT treatment also reversed the characteristics of miniature excitatory post-synaptic currents as well as paired pulse facilitation obsd. in lateral amygdala slices. These results provided further evidence to support the role of the amygdala in characteristic behavioral changes in the rat ASD model. The serotonergic projections that modulate the amygdala function might play a certain role in the development and treatment of behavioral symptoms exhibited in individuals with ASD.
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  14. 14
    Amodeo, D. A., Rivera, E., Dunn, J. T., and Ragozzino, M. E. (2016) M100907 attenuates elevated grooming behavior in the BTBR mouse. Behav. Brain Res. 313, 67– 70,  DOI: 10.1016/j.bbr.2016.06.064
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    14
    M100907 attenuates elevated grooming behavior in the BTBR mouse
    Amodeo, Dionisio A.; Rivera, Elaine; Dunn, Jeffrey T.; Ragozzino, Michael E.
    Behavioural Brain Research (2016), 313 (), 67-70CODEN: BBREDI; ISSN:0166-4328. (Elsevier B.V.)
    Individuals with autism spectrum disorder (ASD) exhibit social-communication deficits along with restricted interests and repetitive behaviors (RRBs). To date, there is a lack of effective treatments to alleviate RRBs. A recent study found that treatment with the 5HT2A receptor antagonist M100907 attenuates a reversal learning deficit in the BTBR mouse model of autism. The BTBR mouse also exhibits elevated grooming behavior which may model stereotyped motor behaviors also obsd. in ASD. The present study examd. whether 5HT2A receptor blockade with M100907 at either 0.01 or 0.1 mg/kg can reduce repetitive grooming in BTBR mice compared to that of vehicle-treated BTBR and C57BL6/J (B6) mice. M100907 at 0.1 mg/kg, but not 0.01 mg/kg, significantly attenuated repetitive grooming in BTBR mice compared to that of vehicle-treated BTBR mice. M100907 at either dose did not affect grooming behavior in B6 mice. To det. whether 0.1 mg/kg M100907 had a more general effect on activity in BTBR mice, a second expt. detd. whether M100907 at 0.1 mg/kg affected locomotor activity in BTBR mice. M100907 treatment in BTBR and B6 mice did not alter locomotor activity compared to that of vehicle-treated BTBR and B6 mice. The present findings taken together with past results suggest that treatment with a 5HT2A receptor antagonist may be effective in ameliorating RRBs in ASD.
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  15. 15
    Amodeo, D. A., Rivera, E., Cook, E. H., Sweeney, J. A., and Ragozzino, M. E. (2017) 5-HT2A receptor blockade in dorsomedial striatum reduces repetitive behaviors in BTBR mice. Genes Brain. Behav. 16, 342– 351,  DOI: 10.1111/gbb.12343
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    15
    5HT2A receptor blockade in dorsomedial striatum reduces repetitive behaviors in BTBR mice
    Amodeo, D. A.; Rivera, E.; Cook, E. H., Jr.; Sweeney, J. A.; Ragozzino, M. E.
    Genes, Brain and Behavior (2017), 16 (3), 342-351CODEN: GBBEAO; ISSN:1601-183X. (Wiley-Blackwell)
    Restricted and repetitive behaviors are a defining feature of autism, which can be expressed as a cognitive flexibility deficit or stereotyped, motor behaviors. There is limited knowledge about the underlying neuropathophysiol. contributing to these behaviors. Previous findings suggest that central 5HT2A receptor activity is altered in autism, while recent work indicates that systemic 5HT2A receptor antagonist treatment reduces repetitive behaviors in an idiopathic model of autism. 5HT2A receptors are expressed in the orbitofrontal cortex and striatum. These two regions have been shown to be altered in autism. The present study investigated whether 5HT2A receptor blockade in the dorsomedial striatum or orbitofrontal cortex in the BTBR mouse strain, an idiopathic model of autism, affects the phenotype related to restricted and repetitive behaviors. Microinfusion of the 5HT2A receptor antagonist, M100907 into the dorsomedial striatum alleviated a reversal learning impairment and attenuated grooming behavior. M100907 infusion into the orbitofrontal cortex increased perseveration during reversal learning and potentiated grooming. These findings suggest that increased 5HT2A receptor activity in the dorsomedial striatum may contribute to behavioral inflexibility and stereotyped behaviors in the BTBR mouse. The 5HT2A receptor signaling in the orbitofrontal cortex may be crit. for inhibiting a previously learned response during reversal learning and expression of stereotyped behavior. The present results suggest which brain areas exhibit abnormalities underlying repetitive behaviors in an idiopathic mouse model of autism, as well as which brain areas systemic treatment with M100907 may principally act on in BTBR mice to attenuate repetitive behaviors.
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  16. 16
    de Bruin, N. M. W. J., van Loevezijn, A., Wicke, K. M., de Haan, M., Venhorst, J., Lange, J. H. M., de Groote, L., van der Neut, M. A. W., Prickaerts, J., Andriambeloson, E. (2016) G. The selective 5-HT6 receptor antagonist SLV has putative cognitive- and social interaction enhancing properties in rodent models of cognitive impairment. Neurobiol. Learn. Mem. 133, 100– 117,  DOI: 10.1016/j.nlm.2016.06.020
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    16
    The selective 5-HT6 receptor antagonist SLV has putative cognitive- and social interaction enhancing properties in rodent models of cognitive impairment
    de Bruin, N. M. W. J.; van Loevezijn, A.; Wicke, K. M.; de Haan, M.; Venhorst, J.; Lange, J. H. M.; de Groote, L.; van der Neut, M. A. W.; Prickaerts, J.; Andriambeloson, E.; Foley, A. G.; van Drimmelen, M.; van der Wetering, M.; Kruse, C. G.
    Neurobiology of Learning and Memory (2016), 133 (), 100-117CODEN: NLMEFR; ISSN:1074-7427. (Elsevier Inc.)
    In the present study, our aim was to investigate whether the novel highly selective 5-hydroxytryptamine6 (5-HT6) receptor antagonist SLV can ameliorate impairments in cognition and social interaction with potential relevance for both schizophrenia and Alzheimer's disease (AD). SLV sub-chronically - treated Wistar rats reared in isolation showed significantly enhanced prepulse inhibition (PPI) and object recognition performance when compared to vehicle - treated rats. In the isolated rats, also a significant redn. in expression of hippocampal neural cell adhesion mol. polysialylation (NCAM-PSA) was found which was ameliorated following treatment with SLV (30 mg/kg). The social engagement deficit in rats exposed in utero (on gestational day 12.5) to valproic acid (VPA) was reversed by treatment with SLV (30 mg/kg). SLV (20 and 30 mg/kg, p.o.) fully reversed MK-801 - induced deficits in the ORT and also scopolamine - induced deficits in both the Object Recognition Task (ORT) and Object Location Task (OLT) in Wistar rats. In addn., a combination of sub-optimal doses of SLV and donepezil attenuated scopolamine-induced ORT deficits. Furthermore, SLV (10 mg/kg, p.o.) reversed spontaneous alternation deficits in the T-maze induced by MK-801 administration in Swiss mice and in aged C57Bl/6J mice. SLV addnl. improved T-Maze spatial learning and passive avoidance learning in Sprague-Dawley rats with amyloid-beta (Aβ) injections into the hippocampus. In contrast, no benefits were found with SLV or the tested ref. compds. (donepezil and RVT-101) on cognitive performance of 12 mo old Tg2576 mice. Also, in the social recognition task, an absence of cognitive enhancing properties was obsd. with SLV on "normal forgetting" in Wistar rats. Finally, anal. of spontaneous inhibitory postsynaptic currents (sIPSCs) frequency recorded from pyramidal cells revealed a redn. in the presence of 1 μM of SLV. In conclusion, SLV was investigated in several rodent animal models and found to be effective at a least ED (LED) of 20 mg/kg and 10 mg/kg (p.o.) in the rat and the mouse, resp.
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  17. 17
    Costa, L., Spatuzza, M., D’Antoni, S., Bonaccorso, C. M., Trovato, C., Musumeci, S. A., Leopoldo, M., Lacivita, E., Catania, M. V., and Ciranna, L. (2012) Activation of 5-HT7 serotonin receptors reverses metabotropic glutamate receptor-mediated synaptic plasticity in wild-type and Fmr1 knockout mice, a model of Fragile X syndrome. Biol. Psychiatry 72, 924– 933,  DOI: 10.1016/j.biopsych.2012.06.008
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    17
    Activation of 5-HT7 Serotonin Receptors Reverses Metabotropic Glutamate Receptor-Mediated Synaptic Plasticity in Wild-Type and Fmr1 Knockout Mice, a Model of Fragile X Syndrome
    Costa, Lara; Spatuzza, Michela; D'Antoni, Simona; Bonaccorso, Carmela M.; Trovato, Chiara; Musumeci, Sebastiano A.; Leopoldo, Marcello; Lacivita, Enza; Catania, Maria V.; Ciranna, Lucia
    Biological Psychiatry (2012), 72 (11), 924-933CODEN: BIPCBF; ISSN:0006-3223. (Elsevier)
    Fragile X syndrome (FXS) is a genetic cause of intellectual disability and autism. Fmr1 knockout (Fmr1 KO) mice, an animal model of FXS, exhibit spatial memory impairment and synapse malfunctioning in the hippocampus, with abnormal enhancement of long-term depression mediated by metabotropic glutamate receptors (mGluR-LTD). The neurotransmitter serotonin (5-HT) modulates hippocampal-dependent learning through serotonin 1A (5-HT1A) and serotonin 7 (5-HT7) receptors; the underlying mechanisms are unknown. We used electrophysiol. to test the effects of 5-HT on mGluR-LTD in wild-type and Fmr1 KO mice and immunocytochem. and biotinylation assay to study related changes of 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid (AMPA) glutamate receptor surface expression. Application of 5-HT or 8-OH-DPAT (a mixed 5-HT1A/5-HT7 agonist) reversed mGluR-LTD in hippocampal slices. Reversal of mGluR-LTD by 8-OH-DPAT persisted in the presence of the 5-HT1A receptor antagonist WAY-100635, was abolished by SB-269970 (5-HT7 receptor antagonist), and was mimicked by LP-211, a novel selective 5-HT7 receptor agonist. Consistently, 8-OH-DPAT decreased mGluR-mediated redn. of AMPA glutamate receptor 2 (GluR2) subunit surface expression in hippocampal slices and cultured hippocampal neurons, an effect mimicked by LP-211 and blocked by SB-269970. In Fmr1 KO mice, mGluR-LTD was abnormally enhanced; similarly to wild-type, 8-OH-DPAT reversed mGluR-LTD and decreased mGluR-induced redn. of surface AMPA receptors, an effect antagonized by SB-269970. Serotonin 7 receptor activation reverses metabotropic glutamate receptor-induced AMPA receptor internalization and LTD both in wild-type and in Fmr1 KO mice, correcting excessive mGluR-LTD. Therefore, selective activation of 5-HT7 receptors may represent a novel strategy in the therapy of FXS.
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  18. 18
    Costa, L., Sardone, L. M., Lacivita, E., Leopoldo, M., and Ciranna, L. (2015) Novel agonists for serotonin 5-HT7 receptors reverse metabotropic glutamate receptor-mediated long-term depression in the hippocampus of wild-type and Fmr1 KO mice, a model of Fragile X Syndrome. Front. Behav. Neurosci. 9, 65
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    18
    Novel agonists for serotonin 5-HT7 receptors reverse metabotropic glutamate receptor-mediated long-term depression in the hippocampus of wild-type and Fmr1 KO mice, a model of Fragile X Syndrome
    Costa, Lara; Sardone, Lara M.; Lacivita, Enza; Leopoldo, Marcello; Ciranna, Lucia
    Frontiers in Behavioral Neuroscience (2015), 9 (), 65/1-65/11CODEN: FBNRAA; ISSN:1662-5153. (Frontiers Media S.A.)
    Serotonin 5-HT7 receptors are expressed in the hippocampus and modulate the excitability of hippocampal neurons. We have previously shown that 5-HT7 receptors modulate glutamate-mediated hippocampal synaptic transmission and long-term synaptic plasticity. In particular, we have shown that activation of 5-HT7 receptors reversed metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD) in wild-type (wt) and in Fmr1 KO mice, a mouse model of Fragile X Syndrome in which mGluR-LTD is abnormally enhanced, suggesting that 5-HT7 receptor agonists might be envisaged as a novel therapeutic strategy for Fragile X Syndrome. In this perspective, we have characterized the basic in vitro pharmacokinetic properties of novel mols. with high binding affinity and selectivity for 5-HT7 receptors and we have tested their effects on synaptic plasticity using patch clamp on acute hippocampal slices. Here we show that LP-211, a high affinity selective agonist of 5-HT7 receptors, reverses mGluR-LTD in wt and Fmr1 KO mice, correcting a synaptic malfunction in the mouse model of Fragile X Syndrome. Among novel putative agonists of 5-HT7 receptors, the compd. BA-10 displayed improved affinity and selectivity for 5-HT7 receptors and improved in vitro pharmacokinetic properties with respect to LP-211. BA-10 significantly reversed mGluR-LTD in the CA3-CA1 synapse in wt and Fmr1KO mice, indicating that BA-10 behaved as a highly effective agonist of 5-HT7 receptors and reduced exaggerated mGluR-LTD in a mouse model of Fragile X Syndrome. On the other side, the compds. RA-7 and PM-20, resp. arising from in vivo metab. of LP-211 and BA-10, had no effect on mGluR-LTD thus did not behave as agonists of 5-HT7 receptors in our conditions. The present results provide information about the structure-activity relationship of novel 5-HT7 receptor agonists and indicate that LP-211 and BA-10 might be used as novel pharmacol. tools for the therapy of Fragile X Syndrome.
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  19. 19
    Costa, L., Sardone, L. M., Bonaccorso, C. M., D’Antoni, S., Spatuzza, M., Gulisano, W., Tropea, M. R., Puzzo, D., Leopoldo, M., Lacivita, E., Catania, M. V., Ciranna, L. (2018) Activation of serotonin 5-HT7 receptors modulates hippocampal synaptic plasticity by stimulation of adenylate cyclases and rescues learning and behavior in a mouse model of fragile X syndrome. Front. Mol. Neurosci. 11, 353,  DOI: 10.3389/fnmol.2018.00353
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    19
    Activation of serotonin 5-HT7 receptors modulates hippocampal synaptic plasticity by stimulation of adenylate cyclases and rescues learning and behavior in a mouse model of fragile X syndrome
    Costa, Lara; Sardone, Lara Maria; Bonaccorso, Carmela Maria; D'Antoni, Simona; Spatuzza, Michela; Gulisano, Walter; Tropea, Maria Rosaria; Puzzo, Daniela; Leopoldo, Marcello; Lacivita, Enza; Catania, Maria Vincenza; Ciranna, Lucia
    Frontiers in Molecular Neuroscience (2018), 11 (), 353CODEN: FMNRAJ; ISSN:1662-5099. (Frontiers Media S.A.)
    We have previously demonstrated that activation of serotonin 5-HT7 receptors (5-HT7R) reverses metabotropic glutamate receptor-mediated long term depression (mGluR-LTD) in the hippocampus of wild-type (WT) and Fmr1 Knockout (KO) mice, a model of Fragile X Syndrome (FXS) in which mGluR-LTD is abnormally enhanced. Here, we have investigated intracellular mechanisms underlying the effect of 5-HT7R activation using patch clamp on hippocampal slices. Furthermore, we have tested whether in vivo administration of LP-211, a selective 5-HT7R agonist, can rescue learning and behavior in Fmr1 KO mice. In the presence of an adenylate cyclase blocker, mGluR-LTD was slightly enhanced in WT and therefore the difference between mGluR-LTD in WT and Fmr1 KO slices was no longer present. Conversely, activation of adenylate cyclase by either forskolin or Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) completely reversed mGluR-LTD in WT and Fmr1 KO. 5-HT7R activation reversed mGluR-LTD in WT and cor. exaggerated mGluR-LTD in Fmr1 KO; this effect was abolished by blockade of either adenylate cyclase or protein kinase A (PKA). Exposure of hippocampal slices to LP-211 caused an increased phosphorylation of extracellular signal regulated kinase (ERK), an intracellular effector involved in mGluR-LTD, in WT mice. Conversely, this effect was barely detectable in Fmr1 KO mice, suggesting that 5-HT7R-mediated reversal of mGluR-LTD does not require ERK stimulation. Finally, an acute in vivo administration of LP-211 improved novel object recognition (NOR) performance in WT and Fmr1 KO mice and reduced stereotyped behavior in Fmr1 KO mice. Our results indicate that mGluR-LTD in WT and Fmr1 KO slices is bidirectionally modulated in conditions of either reduced or enhanced cAMP formation. Activation of 5-HT7 receptors reverses mGluR-LTD by activation of the cAMP/PKA intracellular pathway. Importantly, a systemic administration of a 5-HT7R agonist to Fmr1 KO mice cor. learning deficits and repetitive behavior. We suggest that selective 5-HT7R agonists might become novel pharmacol. tools for FXS therapy.
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  20. 20
    De Filippis, B., Nativio, P., Fabbri, A., Ricceri, L., Adriani, W., Lacivita, E., Leopoldo, M., Passarelli, F., Fuso, A., and Laviola, G. (2014) Pharmacological stimulation of the brain serotonin receptor 7 as a novel therapeutic approach for Rett syndrome. Neuropsychopharmacology 39, 2506– 2518,  DOI: 10.1038/npp.2014.105
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    20
    Pharmacological Stimulation of the Brain Serotonin Receptor 7 as a Novel Therapeutic Approach for Rett Syndrome
    De Filippis, Bianca; Nativio, Paola; Fabbri, Alessia; Ricceri, Laura; Adriani, Walter; Lacivita, Enza; Leopoldo, Marcello; Passarelli, Francesca; Fuso, Andrea; Laviola, Giovanni
    Neuropsychopharmacology (2014), 39 (11), 2506-2518CODEN: NEROEW; ISSN:0893-133X. (Nature Publishing Group)
    Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioral and physiol. symptoms. Mutations in the Me CpG-binding protein 2 gene (MECP2) cause >95% of classic cases, and currently there is no cure for this devastating disorder. The serotonin receptor 7 (5-HT7R) is linked to neuro-physiol. regulation of circadian rhythm, mood, cognition, and synaptic plasticity. We presently report that 5-HT7R d. is consistently reduced in cortical and hippocampal brain areas of symptomatic MeCP2-308 male mice, a RTT model. Systemic repeated treatment with LP-211 (0.25 mg/kg once/day for 7 days), a brain-penetrant selective 5-HT7R agonist, was able to rescue RTT-related defective performance: anxiety-related profiles in a Light/Dark test, motor abilities in a Dowel test, the exploratory behavior in the Marble Burying test, as well as memory in the Novelty Preference task. In the brain of RTT mice, LP-211 also reversed the abnormal activation of PAK and cofilin (key regulators of actin cytoskeleton dynamics) and of the ribosomal protein (rp) S6, whose reduced activation in MECP2 mutant neurons by mTOR is responsible for the altered protein translational control. Present findings indicate that pharmacol. targeting of 5-HT7R improves specific behavioral and mol. manifestations of RTT, thus representing a first step toward the validation of an innovative systemic treatment. Beyond RTT, the latter might be extended to other disorders assocd. with intellectual disability.
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  21. 21
    De Filippis, B., Chiodi, V., Adriani, W., Lacivita, E., Mallozzi, C., Leopoldo, M., Domenici, M. R., Fuso, A., and Laviola, G. (2015) Long-lasting beneficial effects of central serotonin receptor 7 stimulation in female mice modeling Rett syndrome. Front. Behav. Neurosci. 9, 86
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    21
    Long-lasting beneficial effects of central serotonin receptor 7 stimulation in female mice modeling Rett syndrome
    De Filippis, Bianca; Chiodi, Valentina; Adriani, Walter; Lacivita, Enza; Mallozzi, Cinzia; Leopoldo, Marcello; Domenici, Maria Rosaria; Fuso, Andrea; Laviola, Giovanni
    Frontiers in Behavioral Neuroscience (2015), 9 (), 86/1-86/11CODEN: FBNRAA; ISSN:1662-5153. (Frontiers Media S.A.)
    Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioral and physiol. symptoms. Mutations in the Me CpG binding protein 2 gene (MECP2) cause more than 95% of classic cases, and currently there is no cure for this devastating disorder. Recently we have demonstrated that specific behavioral and brain mol. alterations can be rescued in MeCP2-308 male mice, a RTT mouse model, by pharmacol. stimulation of the brain serotonin receptor 7 (5-HT7R). This member of the serotonin receptor family-crucially involved in the regulation of brain structural plasticity and cognitive processes-can be stimulated by systemic repeated treatment with LP-211, a brain-penetrant selective 5-HT7R agonist. The present study extends previous findings by demonstrating that the LP-211 treatment (0.25 mg/kg, once per day for 7 days) rescues RTT-related phenotypic alterations, motor coordination (Dowel test), spatial ref. memory (Barnes maze test) and synaptic plasticity (hippocampal long-term-potentiation) in MeCP2-308 heterozygous female mice, the genetic and hormonal milieu that resembles that of RTT patients. LP-211 also restores the activation of the ribosomal protein (rp) S6, the downstream target of mTOR and S6 kinase, in the hippocampus of RTT female mice. Notably, the beneficial effects on neurobehavioral and mol. parameters of a seven-day long treatment with LP-211 were evident up to 2 mo after the last injection, thus suggesting long-lasting effects on RTT-related impairments. Taken together with our previous study, these results provide compelling preclin. evidence of the potential therapeutic value for RTT of a pharmacol. approach targeting the brain 5-HT7R.
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  22. 22
    Valenti, D., de Bari, L., Vigli, D., Lacivita, E., Leopoldo, M., Laviola, G., Vacca, R. A., and De Filippis, B. (2017) Stimulation of the brain serotonin receptor 7 rescues mitochondrial dysfunction in female mice from two models of Rett syndrome. Neuropharmacology 121, 79– 88,  DOI: 10.1016/j.neuropharm.2017.04.024
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    22
    Stimulation of the brain serotonin receptor 7 rescues mitochondrial dysfunction in female mice from two models of Rett syndrome
    Valenti, Daniela; de Bari, Lidia; Vigli, Daniele; Lacivita, Enza; Leopoldo, Marcello; Laviola, Giovanni; Vacca, Rosa Anna; De Filippis, Bianca
    Neuropharmacology (2017), 121 (), 79-88CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)
    Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioral and physiol. symptoms. Mutations in the Me CpG binding protein 2 gene (MECP2) cause more than 95% of classic cases, and currently there is no cure for this devastating disorder. Recently we have demonstrated that neurobehavioral and brain mol. alterations can be rescued in a RTT mouse model, by pharmacol. stimulation of the brain serotonin receptor 7 (5-HT7R). This member of the serotonin receptor family, crucially involved in the regulation of brain structural plasticity and cognitive processes, can be stimulated by systemic repeated treatment with LP-211, a brain-penetrant selective agonist. The present study extends previous findings by demonstrating that LP-211 treatment (0.25 mg/kg, once per day for 7 days) rescues mitochondrial respiratory chain impairment, oxidative phosphorylation deficiency and the reduced energy status in the brain of heterozygous female mice from two highly validated mouse models of RTT (MeCP2-308 and MeCP2-Bird mice). Moreover, LP-211 treatment completely restored the radical species overprodn. by brain mitochondria in the MeCP2-308 model and partially recovered the oxidative imbalance in the more severely affected MeCP2-Bird model. These results provide the first evidence that RTT brain mitochondrial dysfunction can be rescued targeting the brain 5-HT7R and add compelling preclin. evidence of the potential therapeutic value of LP-211 as a pharmacol. approach for this devastating neurodevelopmental disorder.
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  23. 23
    Vigli, D., Rusconi, L., Valenti, D., La Montanara, P., Cosentino, L., Lacivita, E., Leopoldo, M., Amendola, E., Gross, C., Landsberger, N. (2019) Rescue of prepulse inhibition deficit and brain mitochondrial dysfunction by pharmacological stimulation of the central serotonin receptor 7 in a mouse model of CDKL5 Deficiency Disorder. Neuropharmacology 144, 104– 114,  DOI: 10.1016/j.neuropharm.2018.10.018
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    23
    Rescue of prepulse inhibition deficit and brain mitochondrial dysfunction by pharmacological stimulation of the central serotonin receptor 7 in a mouse model of CDKL5 Deficiency Disorder
    Vigli, Daniele; Rusconi, Laura; Valenti, Daniela; La Montanara, Paolo; Cosentino, Livia; Lacivita, Enza; Leopoldo, Marcello; Amendola, Elena; Gross, Cornelius; Landsberger, Nicoletta; Laviola, Giovanni; Kilstrup-Nielsen, Charlotte; Vacca, Rosa A.; De Filippis, Bianca
    Neuropharmacology (2019), 144 (), 104-114CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)
    Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause CDKL5 Deficiency Disorder (CDD), a rare neurodevelopmental syndrome characterized by severe behavioral and physiol. symptoms. No cure is available for CDD. CDKL5 is a kinase that is abundantly expressed in the brain and plays a crit. role in neurodevelopmental processes, such as neuronal morphogenesis and plasticity. This study provides the first characterization of the neurobehavioural phenotype of 1 yr old Cdkl5-null mice and demonstrates that stimulation of the serotonin receptor 7 (5-HT7R) with the agonist mol. LP-211 (0.25 mg/kg once/day for 7 days) partially rescues the abnormal phenotype and brain mol. alterations in Cdkl5-null male mice. In particular, LP-211 treatment completely normalizes the prepulse inhibition defects obsd. in Cdkl5-null mice and, at a mol. level, restores the abnormal cortical phosphorylation of rpS6, a downstream target of mTOR and S6 kinase, which plays a direct role in regulating protein synthesis. Moreover, we demonstrate for the first time that mitochondria show prominent functional abnormalities in Cdkl5-null mouse brains that can be restored by pharmacol. stimulation of brain 5-HT7R.
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  24. 24
    Kroeze, W. K., Hufeisen, S. J., Popadak, B. A., Renock, S. M., Steinberg, S., Ernsberger, P., Jayathilake, K., Meltzer, H. Y., and Roth, B. L. (2003) H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology 28, 519– 526,  DOI: 10.1038/sj.npp.1300027
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    24
    H1-Histamine Receptor Affinity Predicts Short-Term Weight Gain for Typical and Atypical Antipsychotic Drugs
    Kroeze, Wesley K.; Hufeisen, Sandra J.; Popadak, Beth A.; Renock, Sean M.; Steinberg, SeAnna; Ernsberger, Paul; Jayathilake, Karu; Meltzer, Herbert Y.; Roth, Bryan L.
    Neuropsychopharmacology (2003), 28 (3), 519-526CODEN: NEROEW; ISSN:0893-133X. (Nature Publishing Group)
    As a result of superior efficacy and overall tolerability, atypical antipsychotic drugs have become the treatment of choice for schizophrenia and related disorders, despite their side effects. Wt. gain is a common and potentially serious complication of some antipsychotic drug therapy, and may be accompanied by hyperlipidemia, hypertension and hyperglycemia and, in some extreme cases, diabetic ketoacidosis. The mol. mechanism(s) responsible for antipsychotic drug-induced wt. gain are unknown, but have been hypothesized to be because of interactions of antipsychotic drugs with several neurotransmitter receptors, including 5-HT2A and 5-HT2C serotonin receptors, H1-histamine receptors, α1- and α2-adrenergic receptors, and m3-muscarinic receptors. To det. the receptor(s) likely to be responsible for antipsychotic-drug-induced wt. gain, we screened 17 typical and atypical antipsychotic drugs for binding to 12 neurotransmitter receptors. H1-histamine receptor affinities for this group of typical and atypical antipsychotic drugs were significantly correlated with wt. gain (Spearman ρ=-0.72; p∼0.01), as were affinities for α1A adrenergic (ρ=-0.54; p∼0.05), 5-HT2C (ρ=-0.49; p∼0.05) and 5-HT6 receptors (ρ=-0.54; p∼0.05), whereas eight other receptors' affinities were not. A principal components anal. showed that affinities at the H1, α2A, α2B, 5-HT2A, 5-HT2C, and 5-HT6 receptors were most highly correlated with the first principal component, and affinities for the D2, 5-HT1A, and 5-HT7 receptors were most highly correlated with the second principal component. A discriminant functions anal. showed that affinities for the H1 and α1A receptors were most highly correlated with the discriminant function axis. The discriminant function anal., as well as the affinity for the H1-histamine receptor alone, correctly classified 15 of the 17 drugs into two groups; those that induce wt. gain and those that do not. Because centrally acting H1-histamine receptor antagonists are known to induce wt. gain with chronic use, and because H1-histamine receptor affinities are pos. correlated with wt. gain among typical and atypical antipsychotic drugs, it is recommended that the next generation of atypical antipsychotic drugs be screened to avoid H1-histamine receptors.
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  25. 25
    Witt, N. A., Lee, B., Ghent, K., Zhang, W. Q., Pehrson, A. L., Sánchez, C., and Gould, G. G. (2019) Vortioxetine reduces marble burying but only transiently enhances social interaction preference in adult male BTBR T+Itpr3tf/J mice. ACS Chem. Neurosci. 10, 4319– 4327,  DOI: 10.1021/acschemneuro.9b00386
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    25
    Vortioxetine Reduces Marble Burying but Only Transiently Enhances Social Interaction Preference in Adult Male BTBR T+Itpr3tf/J Mice
    Witt, Nasriya A.; Lee, Benita; Ghent, Kaylee; Zhang, Wynne Q.; Pehrson, Alan L.; Sanchez, Connie; Gould, Georgianna G.
    ACS Chemical Neuroscience (2019), 10 (10), 4319-4327CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
    Vortioxetine is a multi-modal antidepressant with agonist activity at serotonin (5-HT)1A and 5-HT1B receptors that blocks the 5-HT transporter (SERT). Previously in male BTBR T+Itpr3tf/J (BTBR) mice the 5-HT1A agonist buspirone and SERT blocker fluoxetine enhanced social interaction but didn't reduce marble burying. We hypothesized vortioxetine, through SERT and 5-HT1A could improve BTBR sociability, and via 5-HT1B could reduce burying better than a selective SERT blocker. Vortioxetine (5-10 mg/kg) or sertraline (2 mg/kg) were administered 50 min pre-sociability and 75 min pre-marble burying tests. Vortioxetine (10 mg/kg) occupancy (%) was 84±1 for SERT, 31±12 for 5-HT1A and 80±5 for 5-HT1B in brain at 110 min post-injection, and serum oxytocin was 24% lower (p < 0.01) in vortioxetine-treated mice. Vortioxetine enhanced social sniffing, whereas sertraline enhanced overall sociability. However, the vortioxetine-induced increase in social sniffing was transient, as it was lost with 30-60 min pre-test delays in subsequent expts. Vortioxetine, and sertraline reduced BTBR marble burying. Based on vortioxetine occupancy SERT and/or 5-HT1B are more likely to underlie these effects than 5-HT1A occupancy. Overall, vortioxetine has great potential for suppressing restrictive-repetitive behaviors, but appears less promising as a sociability enhancer.
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  26. 26
    Canal, C. E., Felsing, D. E., Liu, Y., Zhu, W., Wood, J. T., Perry, C. K., Vemula, R., and Booth, R. G. (2015) An orally active phenylaminotetralin-chemotype serotonin 5-HT7 and 5-HT1A receptor partial agonist that corrects motor stereotypy in mouse models. ACS Chem. Neurosci. 6, 1259– 1270,  DOI: 10.1021/acschemneuro.5b00099
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    26
    An Orally Active Phenylaminotetralin-Chemotype Serotonin 5-HT7 and 5-HT1A Receptor Partial Agonist That Corrects Motor Stereotypy in Mouse Models
    Canal, Clinton E.; Felsing, Daniel E.; Liu, Yue; Zhu, Wanying; Wood, JodiAnne T.; Perry, Charles K.; Vemula, Rajender; Booth, Raymond G.
    ACS Chemical Neuroscience (2015), 6 (7), 1259-1270CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
    Stereotypy (e.g., repetitive hand waving) is a key phenotype of autism spectrum disorder, Fragile X and Rett syndromes, and other neuropsychiatric disorders, and its severity correlates with cognitive and attention deficits. There are no effective treatments, however, for stereotypy. Perturbation of serotonin (5-HT) neurotransmission contributes to stereotypy, suggesting that distinct 5-HT receptors may be pharmacotherapeutic targets to treat stereotypy and related neuropsychiatric symptoms. For example, preclin. studies indicate that 5-HT7 receptor activation corrects deficits in mouse models of Fragile X and Rett syndromes, and clin. trials for autism are underway with buspirone, a 5-HT1A partial agonist with relevant affinity at 5-HT7 receptors. Herein, we report the synthesis, in vitro mol. pharmacol., behavioral pharmacol., and pharmacokinetic parameters in mice after s.c. and oral administration of (+)-5-(2'-fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine ((+)-5-FPT), a new, dual partial agonist targeting both 5-HT7 (Ki = 5.8 nM, EC50 = 34 nM) and 5-HT1A (Ki = 22 nM, EC50 = 40 nM) receptors. Three unique, heterogeneous mouse models were used to assess the efficacy of (+)-5-FPT to reduce stereotypy: idiopathic jumping in C58/J mice, repetitive body rotations in C57BL/6J mice treated with the NMDA antagonist, MK-801, and repetitive head twitching in C57BL/6J mice treated with the 5-HT2 agonist, DOI. Systemic (+)-5-FPT potently and efficaciously reduced or eliminated stereotypy in each of the mouse models without altering locomotor behavior on its own, and addnl. tests showed that (+)-5-FPT, at the highest behaviorally active dose tested, enhanced social interaction and did not cause behaviors indicative of serotonin syndrome. These data suggest that (+)-5-FPT is a promising medication for treating stereotypy in psychiatric disorders.
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  27. 27
    Armstrong, J. L., Casey, A. B., Saraf, T. S., Mukherjee, M., Booth, R. G., and Canal, C. E. (2020) (S)-5-(2′-Fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine, a serotonin receptor modulator, possesses anticonvulsant, prosocial, and anxiolytic-like properties in an Fmr1 knockout mouse model of fragile X syndrome and autism spectrum disorder. ACS Pharmacol. Transl. Sci. 3, 509– 523,  DOI: 10.1021/acsptsci.9b00101
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    27
    (S)-5-(2'-Fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine, a Serotonin Receptor Modulator, Possesses Anticonvulsant, Prosocial, and Anxiolytic-like Properties in an Fmr1 Knockout Mouse Model of Fragile X Syndrome and Autism Spectrum Disorder
    Armstrong, Jessica L.; Casey, Austen B.; Saraf, Tanishka S.; Mukherjee, Munmun; Booth, Raymond G.; Canal, Clinton E.
    ACS Pharmacology & Translational Science (2020), 3 (3), 509-523CODEN: APTSFN; ISSN:2575-9108. (American Chemical Society)
    Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by intellectual disabilities and a plethora of neuropsychiatric symptoms. FXS is the leading monogenic cause of autism spectrum disorder (ASD), which is defined clin. by repetitive and/or restrictive patterns of behavior and social communication deficits. Epilepsy and anxiety are also common in FXS and ASD. Serotonergic neurons directly innervate and modulate the activity of neurobiol. circuits altered in both disorders, providing a rationale for investigating serotonin receptors (5-HTRs) as targets for FXS and ASD drug discovery. Previously we unveiled an orally active aminotetralin, (S)-5-(2'-fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (FPT), that exhibits partial agonist activity at 5-HT1ARs, 5-HT2CRs, and 5-HT7Rs and that reduces repetitive behaviors and increases social approach behavior in wild-type mice. Here we report that in an Fmr1 knockout mouse model of FXS and ASD, FPT is prophylactic for audiogenic seizures. No FPT-treated mice displayed audiogenic seizures, compared to 73% of vehicle-treated mice. FPT also exhibits anxiolytic-like effects in several assays and increases social interactions in both Fmr1 knockout and wild-type mice. Furthermore, FPT increases c-Fos expression in the basolateral amygdala, which is a preclin. effect produced by anxiolytic medications. Receptor pharmacol. assays show that FPT binds competitively and possesses rapid assocn. and dissocn. kinetics at 5-HT1ARs and 5-HT7Rs, yet has slow assocn. and rapid dissocn. kinetics at 5-HT2CRs. Finally, we reassessed and report FPT's affinity and function at 5-HT1ARs, 5-HT2CRs, and 5-HT7Rs. Collectively, these observations provide mounting support for further development of FPT as a pharmacotherapy for common neuropsychiatric symptoms in FXS and ASD.
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  28. 28
    Hedlund, P. B., Leopoldo, M., Caccia, S., Sarkisyan, G., Fracasso, C., Martelli, G., Lacivita, E., Berardi, F., and Perrone, R. (2010) LP-211 is a brain penetrant selective agonist for the serotonin 5-HT7 receptor. Neurosci. Lett. 481, 12– 16,  DOI: 10.1016/j.neulet.2010.06.036
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    28
    LP-211 is a brain penetrant selective agonist for the serotonin 5-HT7 receptor
    Hedlund, Peter B.; Leopoldo, Marcello; Caccia, Silvio; Sarkisyan, Gor; Fracasso, Claudia; Martelli, Giuliana; Lacivita, Enza; Berardi, Francesco; Perrone, Roberto
    Neuroscience Letters (2010), 481 (1), 12-16CODEN: NELED5; ISSN:0304-3940. (Elsevier Ireland Ltd.)
    We have detd. the pharmacol. profile of the new serotonin 5-HT7 receptor agonist N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (LP-211). Radioligand binding assays were performed on a panel of 5-HT receptor subtypes. The compd. was also evaluated in vivo by examg. its effect on body temp. regulation in mice lacking the 5-HT7 receptor (5-HT7 -/-) and their 5-HT7 +/+ sibling controls. Disposition studies were performed in mice of both genotypes. It was found that LP-211 was brain penetrant and underwent metabolic degrdn. to 1-(2-diphenyl)piperazine (RA-7). In vitro binding assays revealed that RA-7 possessed higher 5-HT7 receptor affinity than LP-211 and a better selectivity profile over a panel of 5-HT receptor subtypes. In vivo it was demonstrated that LP-211, and to a lesser degree RA-7, induced hypothermia in 5-HT7 +/+ but not in 5-HT7 -/- mice. Our results suggest that LP-211 can be used as a 5-HT7 receptor agonist in vivo.
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  29. 29
    Leopoldo, M., Lacivita, E., Contino, M., Colabufo, N. A., Berardi, F., and Perrone, R. (2007) Structure-activity relationship study on N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinehexanamides, a class of 5-HT7 receptor agents. 2. J. Med. Chem. 50, 4214– 4221,  DOI: 10.1021/jm070487n
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    29
    Structure-Activity Relationship Study on N-(1,2,3,4-Tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinehexanamides, a Class of 5-HT7 Receptor Agents. 2
    Leopoldo, Marcello; Lacivita, Enza; Contino, Marialessandra; Colabufo, Nicola A.; Berardi, Francesco; Perrone, Roberto
    Journal of Medicinal Chemistry (2007), 50 (17), 4214-4221CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Here the authors report the synthesis of N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinehexanamides 16-29 that were designed to elucidate both structure-affinity and -activity relations for the 5-HT7 receptor, by targeting the substituent in 2-position of the aryl linked to the piperazine ring. The affinities of 16-29 for 5-HT7, 5-HT1A, 5-HT2A, and D2 receptors were assessed by radioligand binding assays. The intrinsic activities at the 5-HT7 receptor of the most potent compds. were detd. Substituents covering a wide range of electronic, steric, and polar properties were evaluated, revealing a key role on 5-HT7 receptor affinity and intrinsic activity. Certain lipophilic substituents (SCH3, CHMe2, NMe2, CH3, Ph) led to high-affinity agonists, whereas OH and NHCH3 substituents switched intrinsic activity toward antagonism. 4-[2-(1-Methylethyl)phenyl]-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (19), 4-(2-diphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (21), and 4-(2-dimethylaminophenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (22) were identified as potent 5-HT7 receptor agonists (Ki = 0.13-1.1 nM, EC50 = 0.90-1.77 μM), showing selectivity over 5-HT1A, 5-HT2A, and D2 receptors.
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  30. 30
    Salerno, L., Pittalà, V., Modica, M. N., Siracusa, M. A., Intagliata, S., Cagnotto, A., Salmona, M., Kurczab, R., Bojarski, A. J., and Romeo, G. (2014) Structure-activity relationships and molecular modeling studies of novel arylpiperazinylalkyl 2-benzoxazolones and 2-benzothiazolones as 5-HT7 and 5-HT1A receptor ligands. Eur. J. Med. Chem. 85, 716– 726,  DOI: 10.1016/j.ejmech.2014.08.023
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    30
    Structure-activity relationships and molecular modeling studies of novel arylpiperazinylalkyl 2-benzoxazolones and 2-benzothiazolones as 5-HT7 and 5-HT1A receptor ligands
    Salerno, Loredana; Pittala, Valeria; Modica, Maria N.; Siracusa, Maria A.; Intagliata, Sebastiano; Cagnotto, Alfredo; Salmona, Mario; Kurczab, Rafal; Bojarski, Andrzej J.; Romeo, Giuseppe
    European Journal of Medicinal Chemistry (2014), 85 (), 716-726CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
    A novel series of arylpiperazinylalkyl 2-benzoxazolones and 2-benzothiazolones I (X = O, S; n = 4-7; R = C6H5, 2-OMeC6H4, 2-MeC6H4, CH2C6H5, 4-ClC6H4, 3-ClC6H4) was designed, synthesized and tested to evaluate their affinity for the 5-HT7 and 5-HT1A receptors. Compds. with a 2-benzothiazolone nucleus generally had affinity values higher than the corresponding 2-benzoxazolone compds. In particular, derivs. possessing a six or seven carbon chain linker between 2-benzothiazolone and arylpiperazine had Ki values in the subnanomolar range for the 5-HT1A receptor and in the low nanomolar range for the 5-HT7 receptor, indicating that they may be interesting dual ligands. Mol. modeling studies revealed different docking poses for the studied compds. in homol. models of 5-HT1A and 5-HT7 receptors, which explained their exptl. detd. affinities and general low selectivity. Addnl., structural interaction fingerprints anal. identified the important amino acid residues for the specific interactions of long-chain arylpiperazines within the binding pockets of both serotonin receptors.
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  31. 31
    Zajdel, P., Kos, T., Marciniec, K., Satała, G., Canale, V., Kamiński, K., Hołuj, M., Lenda, T., Koralewski, R., Bednarski, M. (2018) Novel multi-target azinesulfonamides of cyclic amine derivatives as potential antipsychotics with pro-social and pro-cognitive effects. Eur. J. Med. Chem. 145, 790– 804,  DOI: 10.1016/j.ejmech.2018.01.002
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    31
    Novel multi-target azinesulfonamides of cyclic amine derivatives as potential antipsychotics with pro-social and pro-cognitive effects
    Zajdel, Pawel; Kos, Tomasz; Marciniec, Krzysztof; Satala, Grzegorz; Canale, Vittorio; Kaminski, Krzysztof; Holuj, Malgorzata; Lenda, Tomasz; Koralewski, Robert; Bednarski, Marek; Nowinski, Leszek; Wojcikowski, Jacek; Daniel, Wladyslawa A.; Nikiforuk, Agnieszka; Nalepa, Irena; Chmielarz, Piotr; Kusmierczyk, Justyna; Bojarski, Andrzej J.; Popik, Piotr
    European Journal of Medicinal Chemistry (2018), 145 (), 790-804CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
    Currently used antipsychotics are characterized by multireceptor mode of action. While antagonism of dopamine D2 receptors is responsible for the alleviation of "pos." symptoms of schizophrenia and the effects at other, particularly serotonergic receptors are necessary for their addnl. therapeutic effects, there is no consensus regarding an "ideal" target engagement. Here, a detailed SAR anal. in a series of 45 novel azinesulfonamides of cyclic amine derivs., involving the aryl-piperazine/piperidine pharmacophore, central alicyclic amine and azinesulfonamide groups has led to the selection of (S)-4-((2-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)pyrrolidin-1-yl)sulfonyl)isoquinoline (62). The polypharmacol. profile of 62, characterized by partial 5-HT1AR agonism, 5-HT2A/5-HT7/D2/D3R antagonism, and blockade of SERT, reduced the "pos."-like, and "neg."-like symptoms of psychoses. Compd. 62 produced no catalepsy, demonstrated a low hyperprolactinemia liability and displayed pro-cognitive effects in the novel object recognition task and attentional set-shifting test. While assocn. of in vitro features with the promising in vivo profile of 62 is still not fully established, its clin. efficacy should be verified in further stages of development.
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  32. 32
    Lacivita, E., Podlewska, S., Speranza, L., Niso, M., Satała, G., Perrone, R., Perrone-Capano, C., Bojarski, A. J., and Leopoldo, M. (2016) Structural modifications of the serotonin 5-HT7 receptor agonist N-(4-cyanophenylmethyl)-4-(2-biphenyl)-1-piperazinehexanamide (LP-211) to improve in vitro microsomal stability: a case study. Eur. J. Med. Chem. 120, 363– 379,  DOI: 10.1016/j.ejmech.2016.05.005
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    32
    Structural modifications of the serotonin 5-HT7 receptor agonist N-(4-cyanophenylmethyl)-4-(2-biphenyl)-1-piperazinehexanamide (LP-211) to improve in vitro microsomal stability: A case study
    Lacivita, Enza; Podlewska, Sabina; Speranza, Luisa; Niso, Mauro; Satala, Grzegorz; Perrone, Roberto; Perrone-Capano, Carla; Bojarski, Andrzej J.; Leopoldo, Marcello
    European Journal of Medicinal Chemistry (2016), 120 (), 363-379CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
    The synthesis of thirty long-chain arylpiperazine, e.g., I analogs of the selective and brain penetrant 5-HT7 receptor agonist LP-211 designed to enhance stability towards microsomal oxidative metab is performed. Commonly used medicinal chem. strategies were used (i.e., redn. of overall lipophilicity, introduction of electron-withdrawing groups, blocking of potential vulnerable sites of metab.), and in vitro microsomal stability was tested. The data shows that the adopted design strategy does not directly translate into improvements in stability. Instead, the metabolic stability of the compds. was related to the presence of specific substituents in well-defined regions of the mol. The collected data allowed for the construction of a machine learning model that, in a given chem. space, is able to describe and quant. predict the metabolic stability of the compds. The majority of the synthesized compds. maintained high affinity for 5-HT7 receptors and showed selectivity towards 5-HT6 and dopamine D2 receptors and different selectivity for 5-HT1A and α1 adrenergic receptors. Compd. N-(4-cyanophenylmethyl)-4-[2-(4-methoxyphenyl)-4-fluorophenyl]-1-piperazinehexanamide showed 3-fold higher in vitro stability towards oxidative metab. than LP-211 and was able to stimulate neurite outgrowth in neuronal primary cultures through the 5-HT7 receptor in a shorter time and at a lower concn. than the agonist LP-211. A preliminary disposition study in mice revealed that compd. N-(4-cyanophenylmethyl)-4-[2-(4-methoxyphenyl)-4-fluorophenyl]-1-piperazinehexanamide was metabolically stable and was able to pass the blood-brain barrier, thus representing a new tool for studying the pharmacotherapeutic potential of 5-HT7 receptor in vivo.
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  33. 33
    Forster, E. A., Cliffe, I. A., Bill, D. J., Dover, G. M., Jones, D., Reilly, Y., and Fletcher, A. (1995) A pharmacological profile of the selective silent 5-HT1A receptor antagonist, WAY-100635. Eur. J. Pharmacol. 281, 81– 88,  DOI: 10.1016/0014-2999(95)00234-C
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    A pharmacological profile of the selective silent 5-HT1A receptor antagonist, WAY-100635
    Forster, Elaine A.; Cliffe, Ian A.; Bill, David J.; Dover, Gillian M.; Jones, Deborah; Reilly, Yvonne; Fletcher, Allan
    European Journal of Pharmacology (1995), 281 (1), 81-8CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier)
    WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohex anecarboxamide trihydrochloride) is an achiral phenylpiperazine deriv. that binds with high affinity and selectivity to the 5-HT1A receptor. WAY-100635 displaced specific binding of the 5-HT1A radioligand, [3H]8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), to rat hippocampal membranes with a pIC50 of 8.87. This represented a greater than 100-fold selectivity relative to binding at other 5-HT receptor subtypes and major neurotransmitter receptor, reuptake and ion channel sites. In functional assays, WAY-100635 was a potent 5-HT1A receptor antagonist, with no evidence of any 5-HT1A receptor agonist or partial agonist activity. In the isolated guinea-pig ileum WAY-100635 was a potent and, at high concns., an insurmountable antagonist of the 5-HT1A receptor agonist action of 5-carboxamidotryptamine, with an apparent pA2 value (at 0.3 nM) of 9.71. WAY-100635 blocked the inhibitory action of 8-OH-DPAT on dorsal raphe neuronal firing in the anesthetized rat at doses which had no inhibitory action per se. In behavioral models, WAY-100635 itself induced no overt behavioral changes but potently antagonized the behavioral syndrome induced by 8-OH-DPAT in the rat and guinea-pig (min. ED = 0.003 mg/kg s.c. and ID50 = 0.01 mg/kg s.c., resp.). WAY-100635 also blocked the hypothermia induced by 8-OH-DPAT in the mouse and rat with ID50 values of 0.01 mg/kg s.c. These data indicate that WAY-100635 will be used as a std. antagonist in further studies of 5-HT1A receptor function.
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  34. 34
    Bojarski, A. J., Paluchowska, M. H., Duszyńska, B., Bugno, R., Kłodzińska, A., Tatarczyńska, E., and Chojnacka-Wójcik, E. (2006) Structure-intrinsic activity relationship studies in the group of 1-imido/amido substituted 4-(4-arylpiperazin-1-yl)cyclohexane derivatives; new, potent 5-HT1A receptor agents with anxiolytic- like activity. Bioorg. Med. Chem. 14, 1391– 1402,  DOI: 10.1016/j.bmc.2005.09.060
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    Structure-intrinsic activity relationship studies in the group of 1-imido/amido substituted 4-(4-arylpiperazin-1-yl)cyclohexane derivatives; new, potent 5-HT1A receptor agents with anxiolytic- like activity
    Bojarski, Andrzej J.; Paluchowska, Maria H.; Duszynska, Beata; Bugno, Ryszard; Klodzinska, Aleksandra; Tatarczynska, Ewa; Chojnacka-Wojcik, Ewa
    Bioorganic & Medicinal Chemistry (2006), 14 (5), 1391-1402CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
    Introduction of 1,4-disubstituted cyclohexane ring in the structure of flexible long chain arylpiperazines resulted in linearly constrained, potent serotonin (5-HT)1A ligands. In order to trace structure-intrinsic activity relationships in this group, a new series of 1-substituted 4-(4-arylpiperazin-1-yl)cyclohexane derivs. with different cyclic imide/amide termini, and their flexible, tetramethylene analogs were synthesized and pharmacol. evaluated for 5-HT1A receptors. In vitro binding expts. revealed that all the compds. were potent 5-HT1A receptor agents (K i = 1.9-74 nM). Some derivs. tested addnl. showed also high affinity for α1-adrenergic receptors (K i = 2.9-101 nM) and for 5-HT7 receptors. Functional in vivo examn. revealed that rigid ligands with o-OCH3 group in the aryl moiety and cyclic imide system in the opposite terminal behaved like postsynaptic 5-HT1A receptor antagonists. On the other hand, unsubstituted, m-Cl, or m-CF3 substituted derivs. as well as those with cyclic amide group in the terminal fragment exhibited agonistic or partial agonistic activity. Three out of four derivs. tested, i.e., postsynaptic 5-HT1A antagonists 9 and 10, and partial agonist 16, showed anxiolytic-like activity in the conflict drinking (Vogel) test in rats.
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    Kumar, J. S., Prabhakaran, J., Majo, V. J., Milak, M. S., Hsiung, S. C., Tamir, H., Simpson, N. R., Van Heertum, R. L., Mann, J. J., and Parsey, R. V. (2007) Synthesis and in vivo evaluation of a novel 5-HT1A receptor agonist radioligand (O-methyl- 11C]2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione in nonhuman primates. Eur. J. Nucl. Med. Mol. Imaging 34, 1050– 1060,  DOI: 10.1007/s00259-006-0324-y
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    Synthesis and in vivo evaluation of a novel 5-HT1A receptor agonist radioligand [O-methyl-11C]2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione in nonhuman primates
    Kumar, J. S. Dileep; Prabhakaran, Jaya; Majo, Vattoly J.; Milak, Matthew S.; Hsiung, Shu-Chi; Tamir, Hadassah; Simpson, Norman R.; Van Heertum, Ronald L.; Mann, J. John; Parsey, Ramin V.
    European Journal of Nuclear Medicine and Molecular Imaging (2007), 34 (7), 1050-1060CODEN: EJNMA6; ISSN:1619-7070. (Springer)
    Purpose: Serotonin1A (5-HT1A) receptors exist in high- and low-affinity states, and agonist ligands bind preferentially to the high-affinity state of the receptor and provide a measure of functional 5-HT1A receptors. Although the antagonist tracers are established PET ligands in clin. studies, a successful 5-HT1A receptor agonist radiotracer in living brain has not been reported. [11C]MPT, our first-generation agonist radiotracer, shows in vivo specificity in baboons; however, its utility is limited owing to slow washout and immeasurable plasma free fraction. Hence we performed structure-activity relationship studies of MPT to optimize a radiotracer that will permit valid quantification of 5-HT1A receptor binding. We now report the synthesis and evaluation of [11C]MMP as an agonist PET tracer for 5-HT1A receptors in baboons. Methods: In vitro binding assays were performed in bovine hippocampal membranes and membranes of CHO cells expressing 5-HT1A receptors. [11C] labeling of MMP was performed by reacting desmethyl-MMP with [11C]CH3OTf. In vivo studies were performed in baboons, and blocking studies were conducted by pretreatment with 5-HT1A receptor ligands WAY-100635 and (±)-8-OH-DPAT. Results: MMP is a selective 5-HT1A receptor agonist (Ki 0.15 nM). Radiosynthesis of [11C]MMP was achieved in 30 ± 5% (n = 15) yield at EOS with a specific activity of 2,600 ± 500 Ci/mmol (n = 12). PET studies in baboons demonstrated specific binding of [11C]MMP to 5-HT1A receptor-enriched brain regions, as confirmed by blockade with WAY-100635 and (±)-8-OH-DPAT. Conclusion: We identified [11C]MMP as an optimal agonist PET tracer that shows quantifiable, specific binding in vivo to 5-HT1A receptors in baboons.
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  36. 36
    López-Rodríguez, M. L., Morcillo, M. J., Fernández, E., Benhamú, B., Tejada, I., Ayala, D., Viso, A., Campillo, M., Pardo, L., Delgado, M. (2005) Synthesis and structure-activity relationships of a new model of arylpiperazines. 8. Computational simulation of ligand-receptor interaction of 5-HT1AR agonists with selectivity over alpha1-adrenoceptors. J. Med. Chem. 48, 2548– 2558,  DOI: 10.1021/jm048999e
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    36
    Synthesis and Structure-Activity Relationships of a New Model of Arylpiperazines. 8.Computational Simulation of Ligand-Receptor Interaction of 5-HT1AR Agonists with Selectivity over α1-Adrenoceptors
    Lopez-Rodriguez, Maria L.; Morcillo, Maria Jose; Fernandez, Esther; Benhamu, Bellinda; Tejada, Ignacio; Ayala, David; Viso, Alma; Campillo, Mercedes; Pardo, Leonardo; Delgado, Mercedes; Manzanares, Jorge; Fuentes, Jose A.
    Journal of Medicinal Chemistry (2005), 48 (7), 2548-2558CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    We have designed and synthesized a new series of arylpiperazines V exhibiting high 5-HT1AR affinity and selectivity over α1-adrenoceptors. The new selective 5-HT1AR ligands contain a hydantoin (m = 0) or diketopiperazine (m = 1) moiety and an arylpiperazine moiety sepd. by one methylene unit (n = 1). The aryl substituent of the piperazine moiety (Ar) consists of different benzofused rings mimicking the favorable voluminous substituents at ortho and meta positions predicted by 3D-QSAR anal. in the previously reported series. In particular, (S)-2-[[4-(naphth-1-yl)piperazin-1-yl]methyl]-1,4-dioxoperhydropyrrolo[1,2-a]pyrazine [CSP-2503] (5-HT1A, Ki = 4.1 nM; α1, Ki > 1000 nM) has been pharmacol. characterized as a 5-HT1AR agonist at somatodendritic and postsynaptic sites, endowed with anxiolytic properties. CSP-2503 is predicted, in computer simulations, to bind Asp3.32 in TMH 3, Thr5.39 and Ser5.42 in TMH 5, and Trp6.48 in TMH 6. We propose that agonists modify, by means of an explicit hydrogen bond, the conformation of Trp6.48 from pointing toward TMH 7, in the inactive gauche+ conformation, to pointing toward the ligand binding site, in the active trans conformation.
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    Cantillon, M., Prakash, A., Alexander, A., Ings, R., Sweitzer, D., and Bhat, L. (2017) Dopamine serotonin stabilizer RP5063: a randomized, double-blind, placebo-controlled multicenter trial of safety and efficacy in exacerbation of schizophrenia or schizoaffective disorder. Schizophr. Res. 189, 126– 133,  DOI: 10.1016/j.schres.2017.01.043
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    Dopamine serotonin stabilizer RP5063: A randomized, double-blind, placebo-controlled multicenter trial of safety and efficacy in exacerbation of schizophrenia or schizoaffective disorder
    Cantillon Marc; Prakash Arul; Alexander Ajay; Ings Robert; Sweitzer Dennis; Bhat Laxminarayan
    Schizophrenia research (2017), 189 (), 126-133 ISSN:.
    The study objectives were to evaluate the efficacy, safety, tolerability, and pharmacokinetics of RP5063 versus placebo. The study was conducted in adults with acute exacerbation of schizophrenia or schizoaffective disorder. This 28-day, multicenter, placebo-controlled, double-blind study randomized 234 subjects to RP5063 15, 30, or 50mg; aripiprazole; or placebo (3:3:3:1:2) once daily. The aripiprazole arm was included solely to show assay sensitivity and was not powered to show efficacy. The primary endpoint was change from baseline to Day 28/EOT (End-of-Treatment) in Positive and Negative Syndrome Scale (PANSS) total score; secondary endpoints included PANSS subscales, improvement ≥1 point on the Clinical Global Impressions-Severity (CGI-S), depression and cognition scales. The primary analysis of PANSS Total showed improvement by a mean (SE) of -20.23 (2.65), -15.42 (2.04), and -19.21 (2.39) in the RP5063 15, 30, and 50mg arms, versus -11.41 (3.45) in the placebo arm. The difference between treatment and placebo reached statistical significance for the 15mg (p=0.021) and 50mg (p=0.016) arms. Improvement with RP5063 was also seen for multiple secondary efficacy outcomes. Discontinuation for any reason was much lower for RP5063 (14%, 25%, 12%) versus placebo (26%) and aripiprazole (35%). The most common treatment-emergent adverse events (TEAE) in the RP5063 groups were insomnia and agitation. There were no significant changes in body weight, electrocardiogram, or incidence of orthostatic hypotension; there was a decrease in blood glucose, lipid profiles, and prolactin levels. In conclusion, the novel dopamine serotonin stabilizer, RP5063 is an efficacious and well-tolerated treatment for acute exacerbation of schizophrenia or schizoaffective disorder.
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    Chen, Y., Wang, S., Xu, X., Liu, X., Yu, M., Zhao, S., Liu, S., Qiu, Y., Zhang, T., Liu, B. F. (2013) Synthesis and biological investigation of coumarin piperazine (piperidine) derivatives as potential multireceptor atypical antipsychotics. J. Med. Chem. 56, 4671– 4690,  DOI: 10.1021/jm400408r
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    38
    Synthesis and Biological Investigation of Coumarin Piperazine (Piperidine) Derivatives as Potential Multireceptor Atypical Antipsychotics
    Chen, Yin; Wang, Songlin; Xu, Xiangqing; Liu, Xin; Yu, Minquan; Zhao, Song; Liu, Shicheng; Qiu, Yinli; Zhang, Tan; Liu, Bi-Feng; Zhang, Guisen
    Journal of Medicinal Chemistry (2013), 56 (11), 4671-4690CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    The discovery and synthesis of potential and novel antipsychotic coumarin derivs., assocd. with potent dopamine D2, D3, and serotonin 5-HT1A and 5-HT2A receptor properties, are the focus of the present article. The most-promising deriv. was 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl)butoxy)-4-methyl-8-chloro-2H-chromen-2-one (I). This deriv. possesses unique pharmacol. features, including high affinity for dopamine D2 and D3 and serotonin 5-HT1A and 5-HT2A receptors. Moreover, it possesses low affinity for 5-HT2C and H1 receptors (to reduce the risk of obesity assocd. with chronic treatment) and hERG channels (to reduce the incidence of torsade de pointes). In animal models, compd. I inhibited apomorphine-induced climbing behavior, MK-801-induced hyperactivity, and the conditioned avoidance response without observable catalepsy at the highest dose tested. Further, fewer preclin. adverse events were noted with I compared with risperidone in assays that measured prolactin secretion and wt. gain. Acceptable pharmacokinetic properties were also noted with I. Taken together, I may constitute a novel class of drugs for the treatment of schizophrenia.
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    Bojarski, A. J. (2006) Pharmacophore models for metabotropic 5-HT receptor ligands. Curr. Top. Med. Chem. 6, 2005– 2026,  DOI: 10.2174/156802606778522186
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    Pharmacophore models for metabotropic 5-HT receptor ligands
    Bojarski, Andrzej J.
    Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2006), 6 (18), 2005-2026CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)
    A review. An overview of pharmacophore models, developed for different subtypes of serotonin receptors belonging to the GPCR family, is presented. Starting with early models for 5-HT1A and 5-HT2 receptor ligands, and ending with the latest ones for 5-HT6- and 5-HT7 receptors, as many as fifty others are briefly summarized. No models have been developed for 5-HT1F-, 5-HT2B- and 5-HT5B receptor ligands, and in the case of 5-HT1E- and 5-HT5ARs only single pilot studies with non-selective tryptamine derivs. are reported. For all the other subtypes of 5-HTRs, various pharmacophore hypotheses - either qual. and/or quant. - are characterized by sets of ligands used for their generation, a templates for alignment, the computational methods applied and, eventually, interfeature distances and/or statistical results - if available.
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    Wager, T. T., Hou, X., Verhoest, P. R., and Villalobos, A. (2016) Central Nervous System Multiparameter Optimization Desirability: application in drug discovery. ACS Chem. Neurosci. 7, 767– 775,  DOI: 10.1021/acschemneuro.6b00029
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    Central Nervous System Multiparameter Optimization Desirability: Application in Drug Discovery
    Wager, Travis T.; Hou, Xinjun; Verhoest, Patrick R.; Villalobos, Anabella
    ACS Chemical Neuroscience (2016), 7 (6), 767-775CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
    Significant progress has been made in prospectively designing mols. using the central nervous system multiparameter optimization (CNS MPO) desirability tool, as evidenced by the anal. reported herein of a second wave of drug candidates that originated after the development and implementation of this tool. This simple-to-use design algorithm has expanded design space for CNS candidates and has further demonstrated the advantages of utilizing a flexible, multiparameter approach in drug discovery rather than individual parameters and hard cutoffs of physicochem. properties. The CNS MPO tool has helped to increase the percentage of compds. nominated for clin. development that exhibit alignment of ADME attributes, cross the blood-brain barrier, and reside in lower-risk safety space (low ClogP and high TPSA). The use of this tool has played a role in reducing the no. of compds. submitted to exploratory toxicity studies and increasing the survival of our drug candidates through regulatory toxicol. into First in Human studies. Overall, the CNS MPO algorithm has helped to improve the prioritization of design ideas and the quality of the compds. nominated for clin. development.
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    Obach, R. S., Baxter, J. G., Liston, T. E., Silber, B. M., Jones, B. C., MacIntyre, F., Rance, D. J., and Wastall, P. (1997) The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data. J. Pharmacol. Exp. Ther. 283, 46– 58
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    The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data
    Obach, R. Scott; Baxter, James G.; Liston, Theodore E.; Silber, B. Michael; Jones, Barry C.; Macintyre, Flona; Rance, David J.; Wastall, Philip
    Journal of Pharmacology and Experimental Therapeutics (1997), 283 (1), 46-58CODEN: JPETAB; ISSN:0022-3565. (Williams & Wilkins)
    A review with 35 refs. We describe a comprehensive retrospective anal. in which the abilities of several methods by which human pharmacokinetic parameters are predicted from preclin. pharmacokinetic data and/or in vitro metab. data were assessed. The prediction methods examd. included both methods from the scientific literature as well as some described in this report for the first time. Four methods were examd. for their ability to predict human vol. of distribution. Three were highly predictive, yielding, on av., predictions that were within 60% to 90% of actual values. Twelve methods were assessed for their utility in predicting clearance. The most successful allometric scaling method yielded clearance predictions that were, on av., within 80% of actual values. The best methods in which in vitro metab. data from human liver microsomes were scaled to in vivo clearance values yielded predicted clearance values that were, on av., within 70% to 80% of actual values. Human t1/2 was predicted by combining predictions of human vol. of distribution and clearance. The best t1/2 prediction methods successfully assigned compds. to appropriate dosing regimen categories (e.g., once daily, twice daily and so forth) 70% to 80% of the time. In addn., correlations between human t1/2 and t1/2 values from preclin. species were also generally successful (72-87%) when used to predict human dosing regimens. In summary, this retrospective anal. has identified several approaches by which human pharmacokinetic data can be predicted from preclin. data. Such approaches should find utility in the drug discovery and development processes in the identification and selection of compds. that will possess appropriate pharmacokinetic characteristics in humans for progression to clin. trials.
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    Kumar, J. S., Majo, V. J., Hsiung, S. C., Millak, M. S., Liu, K. P., Tamir, H., Prabhakaran, J., Simpson, N. R., Van Heertum, R. L., Mann, J. J. (2006) Synthesis and in vivo validation of [O-methyl-11C]2-{4-[4-(7-methoxynaphthalen-1-yl)piperazin-1-yl]butyl}-4-methyl-2H-[1,2,4]triazine-3,5-dione: a novel 5-HT1A receptor agonist positron emission tomography ligand. J. Med. Chem. 49, 125– 134,  DOI: 10.1021/jm050725j
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    Synthesis and in Vivo Validation of [O-Methyl-11C]-2-[4-[4-(7-methoxy-1-naphthalenyl)-1-piperazinyl]butyl]-4-methyl-2H-[1,2,4]triazine-3,5-dione: A Novel 5-HT1A Receptor Agonist Positron Emission Tomography Ligand
    Kumar, J. S. Dileep; Majo, Vattoly J.; Hsiung, Shu-Chi; Millak, Matthew S.; Liu, Kuo-Peing; Tamir, Hadassah; Prabhakaran, Jaya; Simpson, Norman R.; Van Heertum, Ronald L.; Mann, J. John; Parsey, Ramin V.
    Journal of Medicinal Chemistry (2006), 49 (1), 125-134CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Antagonist 5-HT1A PET ligands are available, but an agonist ligand would give more information about signal transduction capacity. Synthesis and in vivo evaluation of [O-methyl-11C]2-{4-[4-(7-methoxy-1-naphthalenyl)-1-piperazinyl]butyl}-4-methyl-2H-[1,2,4]triazine-3,5-dione (I), a potential high affinity (Ki = 1.36 nM) 5-HT1A agonist PET tracer is described. Piperazine I is a 5-HT1A agonist with an EC50 comparable to serotonin, based on cAMP formation and GTPγS binding assays. Radiosynthesis of [11C]-I has been achieved by reacting 2-[4-[4-(7-hydroxy-1-naphthalenyl)-1-piperazinyl]butyl]-4-methyl-2H-[1,2,4]triazine-3,5-dione and [11C]CH3OTf in 25% (n = 15) yield at the end of synthesis (EOS). The chem. and radiochem. purity of [11C]-I were >99% with a specific activity 1500 Ci/mmol (n = 15). PET studies in anesthetized baboon demonstrate [11C]-I specific binding in brain regions rich in 5-HT1A receptors. Binding of [11C]-I was blocked by WAY100635 and 8-OH-DPAT. The regional brain vols. of distribution (VT) of [11C]-I in baboon correlate with [11C]WAY100635 VT in baboon monkeys. These data provide evidence that [11C]-I is the first promising agonist PET tracer for the 5-HT1A receptors.
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    Srinivasa, R. G., Prasanna, K. B. N., Manjunatha, S. G., and Kulkarni, A. K. (2005) Process for the preparation of risperidone, WO2005030772.
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    Lacivita, E., Patarnello, D., Stroth, N., Caroli, A., Niso, M., Contino, M., De Giorgio, P., Di Pilato, P., Colabufo, N. A., Berardi, F. (2012) Investigations on the 1-(2-biphenyl)piperazine motif: identification of new potent and selective ligands for the serotonin7 (5-HT7) receptor with agonist or antagonist action in vitro or ex vivo. J. Med. Chem. 55, 6375– 6380,  DOI: 10.1021/jm3003679
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    Investigations on the 1-(2-Biphenyl)piperazine Motif: Identification of New Potent and Selective Ligands for the Serotonin7 (5-HT7) Receptor with Agonist or Antagonist Action in Vitro or ex Vivo
    Lacivita, Enza; Patarnello, Daniela; Stroth, Nikolas; Caroli, Antonia; Niso, Mauro; Contino, Marialessandra; De Giorgio, Paola; Di Pilato, Pantaleo; Colabufo, Nicola A.; Berardi, Francesco; Perrone, Roberto; Svenningsson, Per; Hedlund, Peter B.; Leopoldo, Marcello
    Journal of Medicinal Chemistry (2012), 55 (14), 6375-6380CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Herein the design, synthesis, and 5-HT7 receptor affinity of a set of 1-(3-biphenyl)- and 1-(2-biphenyl)piperazines are reported. The effect on 5-HT7 affinity of various substituents on the second (distal) Ph ring was analyzed. Several compds. showed 5-HT7 affinities in the nanomolar range and >100-fold selectivity over 5-HT1A and adrenergic α1 receptors. 1-[2-(4-Methoxyphenyl)phenyl]piperazine showed 5-HT7 agonist properties in a guinea pig ileum assay but blocked 5-HT-mediated cAMP accumulation in 5-HT7-expressing HeLa cells.
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    Elgogary, S. R., Hashem, N. M., and Khodeir, M. N. (2015) Synthesis and photooxygenation of linear and angular furocoumarin derivatives as a hydroxyl radical source: psoralen, pseudopsoralen, isopseudopsoralen, and allopsoralen. J. Heteroc. Chem. 52, 506– 512,  DOI: 10.1002/jhet.2084
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    Holloway, B. R., Howe, R., Rao, B. S., and Stribling, D. (1990) Amide derivatives, US4927836.
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    Pendin, D., Norante, R., De Nadai, A., Gherardi, G., Vajente, N., Basso, E., Kaludercic, N., Mammucari, C., Paradisi, C., Pozzan, T. (2019) A synthetic fluorescent mitochondria-targeted sensor for ratiometric imaging of calcium in live cells. Angew. Chem., Int. Ed. 58, 9917– 9922,  DOI: 10.1002/anie.201902272
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    A Synthetic Fluorescent Mitochondria-Targeted Sensor for Ratiometric Imaging of Calcium in Live Cells
    Pendin, Diana; Norante, Rosa; De Nadai, Andrea; Gherardi, Gaia; Vajente, Nicola; Basso, Emy; Kaludercic, Nina; Mammucari, Cristina; Paradisi, Cristina; Pozzan, Tullio; Mattarei, Andrea
    Angewandte Chemie, International Edition (2019), 58 (29), 9917-9922CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Ca2+ handling by mitochondria is crucial for cell life and the direct measure of mitochondrial Ca2+ concn. in living cells is of pivotal interest. Genetically-encoded indicators greatly facilitated this task, however they require demanding delivery procedures. On the other hand, existing mitochondria-targeted synthetic Ca2+ indicators are plagued by several drawbacks, for example, non-specific localization, leakage, toxicity. Here we report the synthesis and characterization of a new fluorescent Ca2+ sensor, named mt-fura-2, obtained by coupling two triphenylphosphonium cations to the mol. backbone of the ratiometric Ca2+ indicator fura-2. Mt-fura-2 binds Ca2+ with a dissocn. const. of ≈1.5 μM in vitro. When loaded in different cell types as acetoxymethyl ester, the probe shows proper mitochondrial localization and accurately measures matrix [Ca2+] variations, proving its superiority over available dyes. We describe the synthesis, characterization and application of mt-fura-2 to cell types where the delivery of genetically-encoded indicators is troublesome.
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    Brown, J. W., Gangloff, A. R., Jennings, A. J., and Vu, P. H. (2010) Poly (ADP-Ribose) Polymerase (PARP) inhibitors, WO2010111626.
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    Kolyasnikova, K. N., Vichuzhanin, M. V., Konstantinopol’skii, M. A., Trofimov, S. S., and Gudasheva, T. A. (2012) Synthesis and pharmacological activity of analogs of the endogenous neuropeptide cycloprolylglycine. Pharm. Chem. J. 46, 96– 102,  DOI: 10.1007/s11094-012-0741-0
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    Synthesis and pharmacological activity of analogs of the endogenous neuropeptide cycloprolylglycine
    Kolyasnikova, K. N.; Vichuzhanin, M. V.; Konstantinopol'skii, M. A.; Trofimov, S. S.; Gudasheva, T. A.
    Pharmaceutical Chemistry Journal (2012), 46 (2), 96-102CODEN: PCJOAU; ISSN:0091-150X. (Springer)
    A series of analogs and homologs of the endogenous cyclic dipeptide cycloprolylglycine were synthesized. The nootropic properties of the synthesized compds. were investigated on an exptl. model of a passive avoidance test with electroshock- or scopolamine-induced amnesia. The anxiolytic activity was examd. by an elevated plus-maze test. It is established that the pharmacophores responsible for the nootropic and anxiolytic activities are different. Hypotheses concerning the structure of the binding regions with the corresponding pharmacol. targets are formulated.
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    Kaar, S. J., Natesan, S., McCutcheon, R., and Howes, O. D. (2020) Antipsychotics: mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology. Neuropharmacology 172, 107704,  DOI: 10.1016/j.neuropharm.2019.107704
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    Antipsychotics: Mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology
    Kaar, Stephen J.; Natesan, Sridhar; McCutcheon, Robert; Howes, Oliver D.
    Neuropharmacology (2020), 172 (), 107704CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)
    A review. Antipsychotic drugs are central to the treatment of schizophrenia and other psychotic disorders but are ineffective for some patients and assocd. with side-effects and nonadherence in others. We review the in vitro, pre-clin., clin. and mol. imaging evidence on the mode of action of antipsychotics and their side-effects. This identifies the key role of striatal dopamine D2 receptor blockade for clin. response, but also for endocrine and motor side-effects, indicating a therapeutic window for D2 blockade. We consider how partial D2/3 receptor agonists fit within this framework, and the role of off-target effects of antipsychotics, particularly at serotonergic, histaminergic, cholinergic, and adrenergic receptors for efficacy and side-effects such as wt. gain, sedation and dysphoria. We review the neurobiol. of schizophrenia relevant to the mode of action of antipsychotics, and for the identification of new treatment targets. This shows elevated striatal dopamine synthesis and release capacity in dorsal regions of the striatum underlies the pos. symptoms of psychosis and suggests reduced dopamine release in cortical regions contributes to cognitive and neg. symptoms. Current drugs act downstream of the major dopamine abnormalities in schizophrenia, and potentially worsen cortical dopamine function. We consider new approaches including targeting dopamine synthesis and storage, autoreceptors, and trace amine receptors, and the cannabinoid, muscarinic, GABAergic and glutamatergic regulation of dopamine neurons, as well as post-synaptic modulation through phosphodiesterase inhibitors. Finally, we consider treatments for cognitive and neg. symptoms such dopamine agonists, nicotinic agents and AMPA modulators before discussing immunol. approaches which may be disease modifying.
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  51. 51
    Lacivita, E., Niso, M., Stama, M. L., Arzuaga, A., Altamura, C., Costa, L., Desaphy, J. F., Ragozzino, M. E., Ciranna, L., and Leopoldo, M. (2020) Privileged scaffold-based design to identify a novel drug-like 5-HT7 receptor-preferring agonist to target fragile X syndrome. Eur. J. Med. Chem. 199, 112395,  DOI: 10.1016/j.ejmech.2020.112395
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    Privileged scaffold-based design to identify a novel drug-like 5-HT7 receptor-preferring agonist to target Fragile X syndrome
    Lacivita, Enza; Niso, Mauro; Stama, Madia Letizia; Arzuaga, Anna; Altamura, Concetta; Costa, Lara; Desaphy, Jean-Francois; Ragozzino, Michael E.; Ciranna, Lucia; Leopoldo, Marcello
    European Journal of Medicinal Chemistry (2020), 199 (), 112395CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
    Recent preclin. studies have shown that activation of the serotonin 5-HT7 receptor has the potential to treat neurodevelopmental disorders such as Fragile X syndrome, a rare disease characterized by autistic features. With the aim to provide the scientific community with diversified drug-like 5-HT7 receptor-preferring agonists, we designed a set of new long-chain arylpiperazines by exploiting structural fragments present in clin. approved drugs or in preclin. candidates (privileged scaffolds). The new compds. were synthesized, tested for their affinity at 5-HT7 and 5-HT1A receptors, and screened for their in vitro stability to microsomal degrdn. and toxicity. Selected compds. were characterized as 5-HT7 receptor-preferring ligands, endowed with high metabolic stability and low toxicity. Compd. 7g emerged as a drug-like 5-HT7 receptor-preferring agonist capable to rescue synaptic plasticity and attenuate stereotyped behavior in a mouse model of Fragile X syndrome.
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  52. 52
    Di, L., Kerns, E. H., Ma, X. J., Huang, Y., and Carter, G. T. (2008) Applications of high throughput microsomal stability assay in drug discovery. Comb. Chem. High Throughput Screening 11, 469– 476,  DOI: 10.2174/138620708784911429
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    Applications of high throughput microsomal stability assay in drug discovery
    Di, Li; Kerns, Edward H.; Ma, Xuewen JoAnn; Huang, Youping; Carter, Guy T.
    Combinatorial Chemistry & High Throughput Screening (2008), 11 (6), 469-476CODEN: CCHSFU; ISSN:1386-2073. (Bentham Science Publishers Ltd.)
    High throughput in vitro microsomal stability assays are widely used in drug discovery as an indicator for in vivo stability, which affects pharmacokinetics. This is based on in-depth research involving a limited no. of model drug-like compds. that are cleared predominantly by cytochrome P 450 metab. However, drug discovery compds. are often not drug-like, are assessed with high throughput assays, and have many potential uncharacterized in vivo clearance mechanisms. Therefore, it is important to det. the correlation between high throughput in vitro microsomal stability data and abbreviated discovery in vivo pharmacokinetics study data for a set of drug discovery compds. to have evidence for how the in vitro assay can be reliably applied by discovery teams for making crit. decisions. In this study the relationship between in vitro single time point high throughput microsomal stability and in vivo clearance from abbreviated drug discovery pharmacokinetics studies was examd. using 306 real world drug discovery compds. The results showed that in vitro Phase I microsomal stability t1/2 is significantly correlated to in vivo clearance. For compds. with low in vitro rat microsomal stability (t1/2 < 15 min), 87% showed high clearance in vivo (CL > 25 mL/min/kg). This demonstrates that high throughput microsomal stability data are very effective in identifying compds. with significant clearance liabilities in vivo. For compds. with high in vitro rat microsomal stability (t1/2 > 15 min), no significant differentiation was obsd. between high and low clearance compds. This is likely owing to other clearance pathways, in addn. to cytochrome P 450 metab. that enhances in vivo clearance. This finding supports the strategy used by medicinal chemists and drug discovery teams of applying the in vitro data to triage compds. for in vivo PK and efficacy studies and guide structural modification to improve metabolic stability. When in vitro and in vivo data are both available for a compd., potential in vivo clearance pathways can be diagnosed to guide further discovery studies.
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  53. 53
    Guscott, M. R., Egan, E., Cook, G. P., Stanton, J. A., Beer, M. S., Rosahl, T. W., Hartmann, S., Kulagowski, J., McAllister, G., Fone, K. F. C. (2003) The hypothermic effect of 5-CT in mice is mediated through the 5-HT7 receptor. Neuropharmacology 44, 1031– 1037,  DOI: 10.1016/S0028-3908(03)00117-5
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    53
    The hypothermic effect of 5-CT in mice is mediated through the 5-HT7 receptor
    Guscott, M. R.; Egan, E.; Cook, G. P.; Stanton, J. A.; Beer, M. S.; Rosahl, T. W.; Hartmann, S.; Kulagowski, J.; McAllister, G.; Fone, K. C. F.; Hutson, P. H.
    Neuropharmacology (2003), 44 (8), 1031-1037CODEN: NEPHBW; ISSN:0028-3908. (Elsevier Science Ltd.)
    The 5-HT7 receptor is a recent addn. to the 5-HT receptor family and to date there is no clear idea as to its potential role in the CNS. The receptor has been mapped by in situ hybridization and 5-HT7-like immunoreactivity and has been detected in discrete areas of the brain including the hypothalamus (Oliver et al., 1999). This suggests the receptor may be involved in temp. regulation and have shown that a selective 5-HT7 receptor antagonist reverses the hypothermic effect of 5-CT in guinea-pigs. The current study confirmed that the 5-HT7 receptor antagonists, SB-269970 (1-30 mg/kg, i.p.) and SB-258719 (5-20 mg/kg, i.p.), but not the 5-HT1A receptor antagonist, WAY 100635(0.1-1 mg/kg, s.c.), or the 5-HT1B/D antagonist, GR127935 (1.25-5 mg/kg, i.p.), reversed the hypothermic effect of 5-CT in mice. In addn. the effect of 5-CT on body temp. was examd. on 5-HT7 receptor null mutant mice. 5-CT (0.1-1 mg/kg, i.p.) significantly reduced rectal temp. in wild-type but not 5-HT7 receptor knockout mice. This suggests that the hypothermic effects of 5-CT are mediated through the 5-HT7 receptor. All procedures were carried out in accordance with the UK Animals (Scientific Procedures) Act (1986).
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    Salonikidis, P. S., Zeug, A., Kobe, F., Ponimaskin, E., and Richter, D. W. (2008) Quantitative measurement of cAMP concentration using an exchange protein directly activated by a cAMP- based FRET-sensor. Biophys. J. 95, 5412– 5423,  DOI: 10.1529/biophysj.107.125666
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    54
    Quantitative measurement of cAMP concentration using an exchange protein directly activated by a cAMP-based FRET-sensor
    Salonikidis, Petrus S.; Zeug, Andre; Kobe, Fritz; Ponimaskin, Evgeni; Richter, Diethelm W.
    Biophysical Journal (2008), 95 (11), 5412-5423CODEN: BIOJAU; ISSN:0006-3495. (Biophysical Society)
    Forster resonance energy transfer (FRET)-based biosensors for the quant. anal. of intracellular signaling, including sensors for monitoring cAMP, are of increasing interest. The measurement of the donor/acceptor emission ratio in tandem biosensors excited at the donor excitation wavelength is a commonly used technique. A general problem, however, is that this ratio varies not only with the changes in cAMP concn. but also with the changes of the ionic environment or other factors affecting the folding probability of the fluorophores. Here, the authors use a spectral FRET anal. on the basis of two excitation wavelengths to obtain a reliable measure of the abs. cAMP concns. with high temporal and spatial resoln. by using an "exchange protein directly activated by cAMP". In this approach, FRET anal. is simplified and does not require addnl. calibration routines. The change in FRET efficiency (E) of the biosensor caused by [cAMP] changes was detd. as ΔE = 15%, whereas E varies between 35% at low and 20% at high [cAMP], allowing quant. measurement of cAMP concn. in the range from 150 nM to 15 μM. The method described is also suitable for other FRET-based biosensors with a 1:1 donor/acceptor stoichiometry. As a proof of principle, the authors measured the spatially resolved cAMP concn. within living cells and detd. the dynamic changes of cAMP levels after stimulation of the Gs-coupled serotonin receptor subtype 7 (5-HT7).
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    Prasad, S., Ponimaskin, E., and Zeug, A. (2019) Serotonin receptor oligomerization regulates cAMP-based signaling. J. Cell. Sci. 132, 1,  DOI: 10.1242/jcs.230334
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    Tran, J. A., Pontillo, J., Arellano, M., White, N. S., Fleck, B. A., Marinkovic, D., Tucci, F. C., Lanier, M., Nelson, J., Saunders, J., Foster, A. C., and Chen, C. (2005) Identification of agonists and antagonists of the human melanocortin-4 receptor from piperazinebenzylamines. Bioorg. Med. Chem. Lett. 15, 833– 837,  DOI: 10.1016/j.bmcl.2004.10.096
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    Identification of agonists and antagonists of the human melanocortin-4 receptor from piperazinebenzylamines
    Tran, Joe A.; Pontillo, Joseph; Arellano, Melissa; White, Nicole S.; Fleck, Beth A.; Marinkovic, Dragan; Tucci, Fabio C.; Lanier, Marion; Nelson, Jodie; Saunders, John; Foster, Alan C.; Chen, Chen
    Bioorganic & Medicinal Chemistry Letters (2005), 15 (3), 833-837CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    SAR studies of a series of piperazinebenzylamines resulted in identification of potent agonists and antagonists of the human melanocortin-4 receptor. Thus, the 1,2,3,4-tetrahydroisoquinolin-1-ylacetyl compd. I and its quinolin-3-ylcarbonyl analog possessed Ki values of 6.3 and 4.5 nM, resp. Interestingly, I was a full agonist with an EC50 value of 31 nM, and 12l was a weak partial agonist (IA = 17%) and functioned as an antagonist (IC50 = 300 nM).
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    Lacivita, E., Niso, M., Hansen, H. D., Di Pilato, P., Herth, M. M., Lehel, S., Ettrup, A., Montenegro, L., Perrone, R., Berardi, F. (2014) Design, synthesis, radiolabeling and in vivo evaluation of potential positron emission tomography (PET) radioligands for brain imaging of the 5-HT7 receptor. Bioorg. Med. Chem. 22, 1736– 1750,  DOI: 10.1016/j.bmc.2014.01.016
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    57
    Design, synthesis, radiolabeling and in vivo evaluation of potential positron emission tomography (PET) radioligands for brain imaging of the 5-HT7 receptor
    Lacivita, Enza; Niso, Mauro; Hansen, Hanne D.; Di Pilato, Pantaleo; Herth, Matthias M.; Lehel, Szabolcs; Ettrup, Anders; Montenegro, Lisa; Perrone, Roberto; Berardi, Francesco; Colabufo, Nicola A.; Leopoldo, Marcello; Knudsen, Gitte M.
    Bioorganic & Medicinal Chemistry (2014), 22 (5), 1736-1750CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
    Here we describe the design, synthesis, and pharmacol. evaluation of a set of compds. structurally related to the high affinity serotonin 5-HT7 receptor agonist N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (6, LP-211). Specific structural modifications were performed in order to maintain affinity for the target receptor and to improve the selectivity over 5-HT1A and adrenergic α1 receptors. The synthesized compds. have chem. features that could enable labeling with a positron emitter radioisotope (carbon-11 or fluorine-18) and lipophilicity within the range considered optimal for brain penetration and low non-specific binding. 4-[2-(4-Methoxyphenyl)phenyl]-N-(pyridin-4-ylmethyl)piperazinehexanamide (23a) and N-pyridin-4-ylmethyl-[3-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]ethoxy]propanamide (26a) were radiolabeled on the methoxy group with carbon-11. Positron emission tomog. (PET) anal. revealed that [11C]-23a and [11C]-26a were P-glycoprotein (P-gp) substrates and rapidly metabolized, resulting in poor brain uptake. These features were not predicted by in vitro tests.
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Cited By

This article is cited by 3 publications.

  1. Margherita Mastromarino, Maria Favia, Igor A. Schepetkin, Lylia N. Kirpotina, Ewa Trojan, Mauro Niso, Antonio Carrieri, Monika Leśkiewicz, Magdalena Regulska, Massimiliano Darida, Francesco Rossignolo, Stefano Fontana, Mark T. Quinn, Agnieszka Basta-Kaim, Marcello Leopoldo, Enza Lacivita. Design, Synthesis, Biological Evaluation, and Computational Studies of Novel Ureidopropanamides as Formyl Peptide Receptor 2 (FPR2) Agonists to Target the Resolution of Inflammation in Central Nervous System Disorders. Journal of Medicinal Chemistry 2022, 65 (6) , 5004-5028. https://doi.org/10.1021/acs.jmedchem.1c02203
  2. Clinton E. Canal, Marcello Leopoldo. The Need To Improve Reporting of the Pharmacological Action of New Molecules. ACS Chemical Neuroscience 2022, 13 (2) , 185-186. https://doi.org/10.1021/acschemneuro.1c00829
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  • Abstract

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    Scheme 1

    Scheme 1. Synthesis of Target Compounds 8a–c and 9a
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    aReagents and conditions: (A) NaH, Br–(CH2)n–X, anhydrous DMF, rt, 12 h, 40–70% yield; (B) 1-arylpiperazine; K2CO3, acetonitrile, reflux overnight, 20–50% yield.

    Scheme 2

    Scheme 2. Synthesis of Target Compounds 11a,ba
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    aReagents and conditions: (A) 1-[2-(4-methoxyphenyl)phenyl]piperazine; K2CO3, acetonitrile, reflux overnight, 61% yield; (B) NaCN, anhydrous DMF, rt, 5 h, quantitative yield; (C) Raney-nickel, H2 (4 atm), MeOH, 50% yield; (D) 2-bromoethanol, CaCO3; reflux, 7 h, 37% yield; (E) PBr3, anhydrous toluene, reflux, 3 h, 65% yield; (F) K2CO3, acetonitrile, reflux overnight, 60% yield.

    Scheme 3

    Scheme 3. Preparation of Target Compounds Featuring the Coumarin Nucleus as the Terminal Fragmenta
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    aReagents and conditions: (A) ethyl acetoacetate; conc. H2SO4, rt, 4 h, 34% yield; (B) 1-[2-(4-methoxyphenyl)phenyl]piperazine; K2CO3, acetonitrile, reflux overnight, 21% yield; (C) NaH, Br–(CH2)n–X, anhydrous DMF, rt, 12 h, 40–60% yield.

    Scheme 4

    Scheme 4. Synthetic Route to Obtain Final Compounds 26aa
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    aReagents and conditions: (A) methyl 2-bromopropionate, K2CO3, acetone, reflux, 16 h, 54% yield; (B) CH3ONa, MeOH, rt, 3 h, 89% yield; (C) 1,2-dibromoethane, K2CO3, anhydrous DMF, 85 °C, 6 h, 70% yield; (D) Fe dust, AcOH, 80 °C, 1 h, 60% yield; (E) 1-[2-(4-methoxyphenyl)phenyl]piperazine; K2CO3, acetonitrile, reflux overnight, 38% yield.

    Scheme 5

    Scheme 5. Synthetic Route to Obtain Final Compounds 26b, 29, and 30a
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    aReagents and conditions: (A) NaH, Br–(CH2)3–Cl, anhydrous DMF, rt, 24 h, 22–42% yield; (B) 1-[2-(4-methoxyphenyl)phenyl]piperazine; K2CO3, acetonitrile, reflux overnight, 20–65% yield. (C) NaH, (R)-glycidyl nosilate, anhydrous DMF, rt, overnight, 41% yield; (D) 1-arylpiperazine; EtOH, reflux, 4 h, 30–54% yield.

    Scheme 6

    Scheme 6. Formation of Target Compounds Bearing the Tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione as Terminal Fragmenta
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    aReagents and conditions: (A) NaH, Br–(CH2)n–Cl, anhydrous DMF, rt, 12 h, 55–75% yield; (B) 1-[2-(4-methoxyphenyl)phenyl]piperazine; K2CO3, acetonitrile, reflux overnight, 43–74% yield.

    Figure 1

    Figure 1. Compounds 8c, 20b, and 29 stimulate 5-HT7R-mediated cAMP production. (A) N1E cells were transfected with cAMP FRET-based biosensor CEPAC and 5-HT7R-mCherry. Cells were stimulated with the compounds, as indicated. Mean values of the cAMP-biosensor response upon stimulation with 8c 20b, and 29 are shown. Stimulation with LP-211 and 5-CT was used as a control. (B) Quantification of the response amplitude and (C) response time shown as the mean ± SEM (3 < N < 6, in each experiment at least 20 cells were analyzed).

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    Figure 2

    Figure 2. Compounds 8c, 20b, and 29 behave as 5-HT1AR agonists in the receptor-mediated cAMP inhibition. (A) N1E cells were transfected with cAMP FRET-based biosensor CEPAC and 5-HT1AR-mCherry. After pretreatment with 1 μM forskolin and 25 μM IBMX, cells were stimulated with the indicated compounds. Each trace shows cAMP response at the single cell. (B) Graphs show changes of cAMP response amplitude relative to pretreatment (mean ± SEM, 3 < N < 6, in each experiment at least 20 cells were analyzed).

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    Figure 3

    Figure 3. Functional assays of inositol phosphate (IP) signaling at cloned human 5-HT2ARs. Concentration–response inhibition curves of 8c, 20b, 29, and risperidone (as reference 5-HT2AR antagonist) on IP production stimulated by 1 μM 5-HT in CHO-K1 cells expressing human 5-HT2ARs. The graph shows data (mean ± SEM) from one experiment performed in duplicate.

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      To det. safety and efficacy of the 5HT1A serotonin partial agonist buspirone on core autism and assocd. features in children with autism spectrum disorder (ASD). Children 2-6 years of age with ASD (N = 166) were randomized to receive placebo or 2.5 or 5.0 mg of buspirone twice daily. The primary objective was to evaluate the effects of 24 wk of buspirone on the Autism Diagnostic Observation Schedule (ADOS) Composite Total Score. Secondary objectives included evaluating the effects of buspirone on social competence, repetitive behaviors, language, sensory dysfunction, and anxiety and to assess side effects. Positron emission tomog. measures of tryptophan metab. and blood serotonin concns. were assessed as predictors of buspirone efficacy. There was no difference in the ADOS Composite Total Score between baseline and 24 wk among the 3 treatment groups (P = .400); however, the ADOS Restricted and Repetitive Behavior score showed a time-by-treatment effect (P = .006); the 2.5-mg buspirone group showed significant improvement (P = .003), whereas placebo and 5.0-mg buspirone groups showed no change. Children in the 2.5-mg buspirone group were more likely to improve if they had fewer foci of increased brain tryptophan metab. on positron emission tomog. (P = .018) or if they showed normal levels of blood serotonin (P = .044). Adverse events did not differ significantly among treatment groups. Treatment with 2.5 mg of buspirone in young children with ASD might be a useful adjunct therapy to target restrictive and repetitive behaviors in conjunction with behavioral interventions. ClinicalTrials.gov: NCT00873509.
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    12. 12
      Gould, G. G., Hensler, J. G., Burke, T. F., Benno, R. H., Onaivi, E. S., and Daws, L. C. (2011) Density and function of central serotonin (5-HT) transporters, 5-HT1A and 5-HT2A receptors, and effects of their targeting on BTBR T+tf/J mouse social behavior. J. Neurochem. 116, 291– 303,  DOI: 10.1111/j.1471-4159.2010.07104.x
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      12
      Density and function of central serotonin (5-HT) transporters, 5-HT1A and 5-HT2A receptors, and effects of their targeting on BTBR T+tf/J mouse social behavior
      Gould, Georgianna G.; Hensler, Julie G.; Burke, Teresa F.; Benno, Robert H.; Onaivi, Emmanuel S.; Daws, Lynette C.
      Journal of Neurochemistry (2011), 116 (2), 291-303CODEN: JONRA9; ISSN:0022-3042. (Wiley-Blackwell)
      BTBR mice are potentially useful tools for autism research because their behavior parallels core social interaction impairments and restricted-repetitive behaviors. Altered regulation of central serotonin (5-HT) neurotransmission may underlie such behavioral deficits. To test this, we compared 5-HT transporter (SERT), 5-HT1A and 5-HT2A receptor densities among BTBR and C57 strains. Autoradiog. [3H] cyanoimipramine (1 nM) binding to SERT was 20-30% lower throughout the adult BTBR brain as compared to C57BL/10J mice. In hippocampal membrane homogenates, [3H] citalopram maximal binding (Bmax) to SERT was 95 fmol/mg protein in BTBR and 171 fmol/mg protein in C57BL/6J mice, and the BTBR dissocn. const. (KD) was 2.0 nM vs. 1.1 in C57BL/6J mice. Hippocampal 5-HT1A and 5-HT2A receptor binding was similar among strains. However, 8-OH-DPAT-stimulated [35S] GTPγS binding in the BTBR hippocampal CA1 region was 28% higher, indicating elevated 5-HT1A capacity to activate G-proteins. In BTBR mice, the SERT blocker, fluoxetine (10 mg/kg) and the 5-HT1A receptor partial-agonist, buspirone (2 mg/kg) enhanced social interactions. The D2/5-HT2 receptor antagonist, risperidone (0.1 mg/kg) reduced marble burying, but failed to improve sociability. Overall, altered SERT and/or 5-HT1A functionality in hippocampus could contribute to the relatively low sociability of BTBR mice.
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    13. 13
      Wang, C.-C., Lin, H.-C., Chan, Y.-H., Gean, P.-W., Yang, Y. K., and Chen, P. S. (2013) 5-HT1A-receptor agonist modified amygdala activity and amygdala-associated social behavior in a valproate-induced rat autism model. Int. J. Neuropsychopharmacol. 16, 2027– 2039,  DOI: 10.1017/S1461145713000473
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      13
      5-HT1A-receptor agonist modified amygdala activity and amygdala-associated social behavior in a valproate-induced rat autism model
      Wang, Chao-Chuan; Lin, Hui-Ching; Chan, Yun-Han; Gean, Po-Wu; Yang, Yen Kung; Chen, Po See
      International Journal of Neuropsychopharmacology (2013), 16 (9), 2027-2039CODEN: IJNUFB; ISSN:1461-1457. (Cambridge University Press)
      Accumulating evidence suggests that dysfunction of the amygdala is related to abnormal fear processing, anxiety, and social behaviors noted in autistic spectrum disorders (ASDs). In addn., studies have shown that disrupted brain serotonin homeostasis is linked to ASD. With a valproate (VPA)-induced rat ASD model, we investigated the possible role of amygdala serotonin homeostasis in autistic phenotypes and further explored the underlying mechanism. We first discovered that the distribution of tryptophan hydroxylase immunoreactivity in the caudal raphe system was modulated on postnatal day (PD) 28 of the VPA-exposed offspring. Then, we found a significantly higher serotonin transporter availability in the amygdala of the VPA-exposed offspring on PD 56 by using single photon emission computed tomog. and computed tomog. co-registration following injection of 123I-labeled 2-((2-(dimethylamino)methyl)phenyl)thio-5-iodophenylamine(123I[ADAM]). Furthermore, treatment with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, increased social interaction and improved fear memory extinction in the VPA-exposed offspring. 8-OH-DPAT treatment also reversed the characteristics of miniature excitatory post-synaptic currents as well as paired pulse facilitation obsd. in lateral amygdala slices. These results provided further evidence to support the role of the amygdala in characteristic behavioral changes in the rat ASD model. The serotonergic projections that modulate the amygdala function might play a certain role in the development and treatment of behavioral symptoms exhibited in individuals with ASD.
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    14. 14
      Amodeo, D. A., Rivera, E., Dunn, J. T., and Ragozzino, M. E. (2016) M100907 attenuates elevated grooming behavior in the BTBR mouse. Behav. Brain Res. 313, 67– 70,  DOI: 10.1016/j.bbr.2016.06.064
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      14
      M100907 attenuates elevated grooming behavior in the BTBR mouse
      Amodeo, Dionisio A.; Rivera, Elaine; Dunn, Jeffrey T.; Ragozzino, Michael E.
      Behavioural Brain Research (2016), 313 (), 67-70CODEN: BBREDI; ISSN:0166-4328. (Elsevier B.V.)
      Individuals with autism spectrum disorder (ASD) exhibit social-communication deficits along with restricted interests and repetitive behaviors (RRBs). To date, there is a lack of effective treatments to alleviate RRBs. A recent study found that treatment with the 5HT2A receptor antagonist M100907 attenuates a reversal learning deficit in the BTBR mouse model of autism. The BTBR mouse also exhibits elevated grooming behavior which may model stereotyped motor behaviors also obsd. in ASD. The present study examd. whether 5HT2A receptor blockade with M100907 at either 0.01 or 0.1 mg/kg can reduce repetitive grooming in BTBR mice compared to that of vehicle-treated BTBR and C57BL6/J (B6) mice. M100907 at 0.1 mg/kg, but not 0.01 mg/kg, significantly attenuated repetitive grooming in BTBR mice compared to that of vehicle-treated BTBR mice. M100907 at either dose did not affect grooming behavior in B6 mice. To det. whether 0.1 mg/kg M100907 had a more general effect on activity in BTBR mice, a second expt. detd. whether M100907 at 0.1 mg/kg affected locomotor activity in BTBR mice. M100907 treatment in BTBR and B6 mice did not alter locomotor activity compared to that of vehicle-treated BTBR and B6 mice. The present findings taken together with past results suggest that treatment with a 5HT2A receptor antagonist may be effective in ameliorating RRBs in ASD.
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    15. 15
      Amodeo, D. A., Rivera, E., Cook, E. H., Sweeney, J. A., and Ragozzino, M. E. (2017) 5-HT2A receptor blockade in dorsomedial striatum reduces repetitive behaviors in BTBR mice. Genes Brain. Behav. 16, 342– 351,  DOI: 10.1111/gbb.12343
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      15
      5HT2A receptor blockade in dorsomedial striatum reduces repetitive behaviors in BTBR mice
      Amodeo, D. A.; Rivera, E.; Cook, E. H., Jr.; Sweeney, J. A.; Ragozzino, M. E.
      Genes, Brain and Behavior (2017), 16 (3), 342-351CODEN: GBBEAO; ISSN:1601-183X. (Wiley-Blackwell)
      Restricted and repetitive behaviors are a defining feature of autism, which can be expressed as a cognitive flexibility deficit or stereotyped, motor behaviors. There is limited knowledge about the underlying neuropathophysiol. contributing to these behaviors. Previous findings suggest that central 5HT2A receptor activity is altered in autism, while recent work indicates that systemic 5HT2A receptor antagonist treatment reduces repetitive behaviors in an idiopathic model of autism. 5HT2A receptors are expressed in the orbitofrontal cortex and striatum. These two regions have been shown to be altered in autism. The present study investigated whether 5HT2A receptor blockade in the dorsomedial striatum or orbitofrontal cortex in the BTBR mouse strain, an idiopathic model of autism, affects the phenotype related to restricted and repetitive behaviors. Microinfusion of the 5HT2A receptor antagonist, M100907 into the dorsomedial striatum alleviated a reversal learning impairment and attenuated grooming behavior. M100907 infusion into the orbitofrontal cortex increased perseveration during reversal learning and potentiated grooming. These findings suggest that increased 5HT2A receptor activity in the dorsomedial striatum may contribute to behavioral inflexibility and stereotyped behaviors in the BTBR mouse. The 5HT2A receptor signaling in the orbitofrontal cortex may be crit. for inhibiting a previously learned response during reversal learning and expression of stereotyped behavior. The present results suggest which brain areas exhibit abnormalities underlying repetitive behaviors in an idiopathic mouse model of autism, as well as which brain areas systemic treatment with M100907 may principally act on in BTBR mice to attenuate repetitive behaviors.
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    16. 16
      de Bruin, N. M. W. J., van Loevezijn, A., Wicke, K. M., de Haan, M., Venhorst, J., Lange, J. H. M., de Groote, L., van der Neut, M. A. W., Prickaerts, J., Andriambeloson, E. (2016) G. The selective 5-HT6 receptor antagonist SLV has putative cognitive- and social interaction enhancing properties in rodent models of cognitive impairment. Neurobiol. Learn. Mem. 133, 100– 117,  DOI: 10.1016/j.nlm.2016.06.020
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      16
      The selective 5-HT6 receptor antagonist SLV has putative cognitive- and social interaction enhancing properties in rodent models of cognitive impairment
      de Bruin, N. M. W. J.; van Loevezijn, A.; Wicke, K. M.; de Haan, M.; Venhorst, J.; Lange, J. H. M.; de Groote, L.; van der Neut, M. A. W.; Prickaerts, J.; Andriambeloson, E.; Foley, A. G.; van Drimmelen, M.; van der Wetering, M.; Kruse, C. G.
      Neurobiology of Learning and Memory (2016), 133 (), 100-117CODEN: NLMEFR; ISSN:1074-7427. (Elsevier Inc.)
      In the present study, our aim was to investigate whether the novel highly selective 5-hydroxytryptamine6 (5-HT6) receptor antagonist SLV can ameliorate impairments in cognition and social interaction with potential relevance for both schizophrenia and Alzheimer's disease (AD). SLV sub-chronically - treated Wistar rats reared in isolation showed significantly enhanced prepulse inhibition (PPI) and object recognition performance when compared to vehicle - treated rats. In the isolated rats, also a significant redn. in expression of hippocampal neural cell adhesion mol. polysialylation (NCAM-PSA) was found which was ameliorated following treatment with SLV (30 mg/kg). The social engagement deficit in rats exposed in utero (on gestational day 12.5) to valproic acid (VPA) was reversed by treatment with SLV (30 mg/kg). SLV (20 and 30 mg/kg, p.o.) fully reversed MK-801 - induced deficits in the ORT and also scopolamine - induced deficits in both the Object Recognition Task (ORT) and Object Location Task (OLT) in Wistar rats. In addn., a combination of sub-optimal doses of SLV and donepezil attenuated scopolamine-induced ORT deficits. Furthermore, SLV (10 mg/kg, p.o.) reversed spontaneous alternation deficits in the T-maze induced by MK-801 administration in Swiss mice and in aged C57Bl/6J mice. SLV addnl. improved T-Maze spatial learning and passive avoidance learning in Sprague-Dawley rats with amyloid-beta (Aβ) injections into the hippocampus. In contrast, no benefits were found with SLV or the tested ref. compds. (donepezil and RVT-101) on cognitive performance of 12 mo old Tg2576 mice. Also, in the social recognition task, an absence of cognitive enhancing properties was obsd. with SLV on "normal forgetting" in Wistar rats. Finally, anal. of spontaneous inhibitory postsynaptic currents (sIPSCs) frequency recorded from pyramidal cells revealed a redn. in the presence of 1 μM of SLV. In conclusion, SLV was investigated in several rodent animal models and found to be effective at a least ED (LED) of 20 mg/kg and 10 mg/kg (p.o.) in the rat and the mouse, resp.
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    17. 17
      Costa, L., Spatuzza, M., D’Antoni, S., Bonaccorso, C. M., Trovato, C., Musumeci, S. A., Leopoldo, M., Lacivita, E., Catania, M. V., and Ciranna, L. (2012) Activation of 5-HT7 serotonin receptors reverses metabotropic glutamate receptor-mediated synaptic plasticity in wild-type and Fmr1 knockout mice, a model of Fragile X syndrome. Biol. Psychiatry 72, 924– 933,  DOI: 10.1016/j.biopsych.2012.06.008
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      17
      Activation of 5-HT7 Serotonin Receptors Reverses Metabotropic Glutamate Receptor-Mediated Synaptic Plasticity in Wild-Type and Fmr1 Knockout Mice, a Model of Fragile X Syndrome
      Costa, Lara; Spatuzza, Michela; D'Antoni, Simona; Bonaccorso, Carmela M.; Trovato, Chiara; Musumeci, Sebastiano A.; Leopoldo, Marcello; Lacivita, Enza; Catania, Maria V.; Ciranna, Lucia
      Biological Psychiatry (2012), 72 (11), 924-933CODEN: BIPCBF; ISSN:0006-3223. (Elsevier)
      Fragile X syndrome (FXS) is a genetic cause of intellectual disability and autism. Fmr1 knockout (Fmr1 KO) mice, an animal model of FXS, exhibit spatial memory impairment and synapse malfunctioning in the hippocampus, with abnormal enhancement of long-term depression mediated by metabotropic glutamate receptors (mGluR-LTD). The neurotransmitter serotonin (5-HT) modulates hippocampal-dependent learning through serotonin 1A (5-HT1A) and serotonin 7 (5-HT7) receptors; the underlying mechanisms are unknown. We used electrophysiol. to test the effects of 5-HT on mGluR-LTD in wild-type and Fmr1 KO mice and immunocytochem. and biotinylation assay to study related changes of 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid (AMPA) glutamate receptor surface expression. Application of 5-HT or 8-OH-DPAT (a mixed 5-HT1A/5-HT7 agonist) reversed mGluR-LTD in hippocampal slices. Reversal of mGluR-LTD by 8-OH-DPAT persisted in the presence of the 5-HT1A receptor antagonist WAY-100635, was abolished by SB-269970 (5-HT7 receptor antagonist), and was mimicked by LP-211, a novel selective 5-HT7 receptor agonist. Consistently, 8-OH-DPAT decreased mGluR-mediated redn. of AMPA glutamate receptor 2 (GluR2) subunit surface expression in hippocampal slices and cultured hippocampal neurons, an effect mimicked by LP-211 and blocked by SB-269970. In Fmr1 KO mice, mGluR-LTD was abnormally enhanced; similarly to wild-type, 8-OH-DPAT reversed mGluR-LTD and decreased mGluR-induced redn. of surface AMPA receptors, an effect antagonized by SB-269970. Serotonin 7 receptor activation reverses metabotropic glutamate receptor-induced AMPA receptor internalization and LTD both in wild-type and in Fmr1 KO mice, correcting excessive mGluR-LTD. Therefore, selective activation of 5-HT7 receptors may represent a novel strategy in the therapy of FXS.
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    18. 18
      Costa, L., Sardone, L. M., Lacivita, E., Leopoldo, M., and Ciranna, L. (2015) Novel agonists for serotonin 5-HT7 receptors reverse metabotropic glutamate receptor-mediated long-term depression in the hippocampus of wild-type and Fmr1 KO mice, a model of Fragile X Syndrome. Front. Behav. Neurosci. 9, 65
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      18
      Novel agonists for serotonin 5-HT7 receptors reverse metabotropic glutamate receptor-mediated long-term depression in the hippocampus of wild-type and Fmr1 KO mice, a model of Fragile X Syndrome
      Costa, Lara; Sardone, Lara M.; Lacivita, Enza; Leopoldo, Marcello; Ciranna, Lucia
      Frontiers in Behavioral Neuroscience (2015), 9 (), 65/1-65/11CODEN: FBNRAA; ISSN:1662-5153. (Frontiers Media S.A.)
      Serotonin 5-HT7 receptors are expressed in the hippocampus and modulate the excitability of hippocampal neurons. We have previously shown that 5-HT7 receptors modulate glutamate-mediated hippocampal synaptic transmission and long-term synaptic plasticity. In particular, we have shown that activation of 5-HT7 receptors reversed metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD) in wild-type (wt) and in Fmr1 KO mice, a mouse model of Fragile X Syndrome in which mGluR-LTD is abnormally enhanced, suggesting that 5-HT7 receptor agonists might be envisaged as a novel therapeutic strategy for Fragile X Syndrome. In this perspective, we have characterized the basic in vitro pharmacokinetic properties of novel mols. with high binding affinity and selectivity for 5-HT7 receptors and we have tested their effects on synaptic plasticity using patch clamp on acute hippocampal slices. Here we show that LP-211, a high affinity selective agonist of 5-HT7 receptors, reverses mGluR-LTD in wt and Fmr1 KO mice, correcting a synaptic malfunction in the mouse model of Fragile X Syndrome. Among novel putative agonists of 5-HT7 receptors, the compd. BA-10 displayed improved affinity and selectivity for 5-HT7 receptors and improved in vitro pharmacokinetic properties with respect to LP-211. BA-10 significantly reversed mGluR-LTD in the CA3-CA1 synapse in wt and Fmr1KO mice, indicating that BA-10 behaved as a highly effective agonist of 5-HT7 receptors and reduced exaggerated mGluR-LTD in a mouse model of Fragile X Syndrome. On the other side, the compds. RA-7 and PM-20, resp. arising from in vivo metab. of LP-211 and BA-10, had no effect on mGluR-LTD thus did not behave as agonists of 5-HT7 receptors in our conditions. The present results provide information about the structure-activity relationship of novel 5-HT7 receptor agonists and indicate that LP-211 and BA-10 might be used as novel pharmacol. tools for the therapy of Fragile X Syndrome.
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    19. 19
      Costa, L., Sardone, L. M., Bonaccorso, C. M., D’Antoni, S., Spatuzza, M., Gulisano, W., Tropea, M. R., Puzzo, D., Leopoldo, M., Lacivita, E., Catania, M. V., Ciranna, L. (2018) Activation of serotonin 5-HT7 receptors modulates hippocampal synaptic plasticity by stimulation of adenylate cyclases and rescues learning and behavior in a mouse model of fragile X syndrome. Front. Mol. Neurosci. 11, 353,  DOI: 10.3389/fnmol.2018.00353
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      19
      Activation of serotonin 5-HT7 receptors modulates hippocampal synaptic plasticity by stimulation of adenylate cyclases and rescues learning and behavior in a mouse model of fragile X syndrome
      Costa, Lara; Sardone, Lara Maria; Bonaccorso, Carmela Maria; D'Antoni, Simona; Spatuzza, Michela; Gulisano, Walter; Tropea, Maria Rosaria; Puzzo, Daniela; Leopoldo, Marcello; Lacivita, Enza; Catania, Maria Vincenza; Ciranna, Lucia
      Frontiers in Molecular Neuroscience (2018), 11 (), 353CODEN: FMNRAJ; ISSN:1662-5099. (Frontiers Media S.A.)
      We have previously demonstrated that activation of serotonin 5-HT7 receptors (5-HT7R) reverses metabotropic glutamate receptor-mediated long term depression (mGluR-LTD) in the hippocampus of wild-type (WT) and Fmr1 Knockout (KO) mice, a model of Fragile X Syndrome (FXS) in which mGluR-LTD is abnormally enhanced. Here, we have investigated intracellular mechanisms underlying the effect of 5-HT7R activation using patch clamp on hippocampal slices. Furthermore, we have tested whether in vivo administration of LP-211, a selective 5-HT7R agonist, can rescue learning and behavior in Fmr1 KO mice. In the presence of an adenylate cyclase blocker, mGluR-LTD was slightly enhanced in WT and therefore the difference between mGluR-LTD in WT and Fmr1 KO slices was no longer present. Conversely, activation of adenylate cyclase by either forskolin or Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) completely reversed mGluR-LTD in WT and Fmr1 KO. 5-HT7R activation reversed mGluR-LTD in WT and cor. exaggerated mGluR-LTD in Fmr1 KO; this effect was abolished by blockade of either adenylate cyclase or protein kinase A (PKA). Exposure of hippocampal slices to LP-211 caused an increased phosphorylation of extracellular signal regulated kinase (ERK), an intracellular effector involved in mGluR-LTD, in WT mice. Conversely, this effect was barely detectable in Fmr1 KO mice, suggesting that 5-HT7R-mediated reversal of mGluR-LTD does not require ERK stimulation. Finally, an acute in vivo administration of LP-211 improved novel object recognition (NOR) performance in WT and Fmr1 KO mice and reduced stereotyped behavior in Fmr1 KO mice. Our results indicate that mGluR-LTD in WT and Fmr1 KO slices is bidirectionally modulated in conditions of either reduced or enhanced cAMP formation. Activation of 5-HT7 receptors reverses mGluR-LTD by activation of the cAMP/PKA intracellular pathway. Importantly, a systemic administration of a 5-HT7R agonist to Fmr1 KO mice cor. learning deficits and repetitive behavior. We suggest that selective 5-HT7R agonists might become novel pharmacol. tools for FXS therapy.
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    20. 20
      De Filippis, B., Nativio, P., Fabbri, A., Ricceri, L., Adriani, W., Lacivita, E., Leopoldo, M., Passarelli, F., Fuso, A., and Laviola, G. (2014) Pharmacological stimulation of the brain serotonin receptor 7 as a novel therapeutic approach for Rett syndrome. Neuropsychopharmacology 39, 2506– 2518,  DOI: 10.1038/npp.2014.105
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      20
      Pharmacological Stimulation of the Brain Serotonin Receptor 7 as a Novel Therapeutic Approach for Rett Syndrome
      De Filippis, Bianca; Nativio, Paola; Fabbri, Alessia; Ricceri, Laura; Adriani, Walter; Lacivita, Enza; Leopoldo, Marcello; Passarelli, Francesca; Fuso, Andrea; Laviola, Giovanni
      Neuropsychopharmacology (2014), 39 (11), 2506-2518CODEN: NEROEW; ISSN:0893-133X. (Nature Publishing Group)
      Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioral and physiol. symptoms. Mutations in the Me CpG-binding protein 2 gene (MECP2) cause >95% of classic cases, and currently there is no cure for this devastating disorder. The serotonin receptor 7 (5-HT7R) is linked to neuro-physiol. regulation of circadian rhythm, mood, cognition, and synaptic plasticity. We presently report that 5-HT7R d. is consistently reduced in cortical and hippocampal brain areas of symptomatic MeCP2-308 male mice, a RTT model. Systemic repeated treatment with LP-211 (0.25 mg/kg once/day for 7 days), a brain-penetrant selective 5-HT7R agonist, was able to rescue RTT-related defective performance: anxiety-related profiles in a Light/Dark test, motor abilities in a Dowel test, the exploratory behavior in the Marble Burying test, as well as memory in the Novelty Preference task. In the brain of RTT mice, LP-211 also reversed the abnormal activation of PAK and cofilin (key regulators of actin cytoskeleton dynamics) and of the ribosomal protein (rp) S6, whose reduced activation in MECP2 mutant neurons by mTOR is responsible for the altered protein translational control. Present findings indicate that pharmacol. targeting of 5-HT7R improves specific behavioral and mol. manifestations of RTT, thus representing a first step toward the validation of an innovative systemic treatment. Beyond RTT, the latter might be extended to other disorders assocd. with intellectual disability.
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    21. 21
      De Filippis, B., Chiodi, V., Adriani, W., Lacivita, E., Mallozzi, C., Leopoldo, M., Domenici, M. R., Fuso, A., and Laviola, G. (2015) Long-lasting beneficial effects of central serotonin receptor 7 stimulation in female mice modeling Rett syndrome. Front. Behav. Neurosci. 9, 86
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      21
      Long-lasting beneficial effects of central serotonin receptor 7 stimulation in female mice modeling Rett syndrome
      De Filippis, Bianca; Chiodi, Valentina; Adriani, Walter; Lacivita, Enza; Mallozzi, Cinzia; Leopoldo, Marcello; Domenici, Maria Rosaria; Fuso, Andrea; Laviola, Giovanni
      Frontiers in Behavioral Neuroscience (2015), 9 (), 86/1-86/11CODEN: FBNRAA; ISSN:1662-5153. (Frontiers Media S.A.)
      Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioral and physiol. symptoms. Mutations in the Me CpG binding protein 2 gene (MECP2) cause more than 95% of classic cases, and currently there is no cure for this devastating disorder. Recently we have demonstrated that specific behavioral and brain mol. alterations can be rescued in MeCP2-308 male mice, a RTT mouse model, by pharmacol. stimulation of the brain serotonin receptor 7 (5-HT7R). This member of the serotonin receptor family-crucially involved in the regulation of brain structural plasticity and cognitive processes-can be stimulated by systemic repeated treatment with LP-211, a brain-penetrant selective 5-HT7R agonist. The present study extends previous findings by demonstrating that the LP-211 treatment (0.25 mg/kg, once per day for 7 days) rescues RTT-related phenotypic alterations, motor coordination (Dowel test), spatial ref. memory (Barnes maze test) and synaptic plasticity (hippocampal long-term-potentiation) in MeCP2-308 heterozygous female mice, the genetic and hormonal milieu that resembles that of RTT patients. LP-211 also restores the activation of the ribosomal protein (rp) S6, the downstream target of mTOR and S6 kinase, in the hippocampus of RTT female mice. Notably, the beneficial effects on neurobehavioral and mol. parameters of a seven-day long treatment with LP-211 were evident up to 2 mo after the last injection, thus suggesting long-lasting effects on RTT-related impairments. Taken together with our previous study, these results provide compelling preclin. evidence of the potential therapeutic value for RTT of a pharmacol. approach targeting the brain 5-HT7R.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsV2htL7N&md5=2ceb672cfb7eaadae64c42e68412f818
    22. 22
      Valenti, D., de Bari, L., Vigli, D., Lacivita, E., Leopoldo, M., Laviola, G., Vacca, R. A., and De Filippis, B. (2017) Stimulation of the brain serotonin receptor 7 rescues mitochondrial dysfunction in female mice from two models of Rett syndrome. Neuropharmacology 121, 79– 88,  DOI: 10.1016/j.neuropharm.2017.04.024
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      22
      Stimulation of the brain serotonin receptor 7 rescues mitochondrial dysfunction in female mice from two models of Rett syndrome
      Valenti, Daniela; de Bari, Lidia; Vigli, Daniele; Lacivita, Enza; Leopoldo, Marcello; Laviola, Giovanni; Vacca, Rosa Anna; De Filippis, Bianca
      Neuropharmacology (2017), 121 (), 79-88CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)
      Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioral and physiol. symptoms. Mutations in the Me CpG binding protein 2 gene (MECP2) cause more than 95% of classic cases, and currently there is no cure for this devastating disorder. Recently we have demonstrated that neurobehavioral and brain mol. alterations can be rescued in a RTT mouse model, by pharmacol. stimulation of the brain serotonin receptor 7 (5-HT7R). This member of the serotonin receptor family, crucially involved in the regulation of brain structural plasticity and cognitive processes, can be stimulated by systemic repeated treatment with LP-211, a brain-penetrant selective agonist. The present study extends previous findings by demonstrating that LP-211 treatment (0.25 mg/kg, once per day for 7 days) rescues mitochondrial respiratory chain impairment, oxidative phosphorylation deficiency and the reduced energy status in the brain of heterozygous female mice from two highly validated mouse models of RTT (MeCP2-308 and MeCP2-Bird mice). Moreover, LP-211 treatment completely restored the radical species overprodn. by brain mitochondria in the MeCP2-308 model and partially recovered the oxidative imbalance in the more severely affected MeCP2-Bird model. These results provide the first evidence that RTT brain mitochondrial dysfunction can be rescued targeting the brain 5-HT7R and add compelling preclin. evidence of the potential therapeutic value of LP-211 as a pharmacol. approach for this devastating neurodevelopmental disorder.
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    23. 23
      Vigli, D., Rusconi, L., Valenti, D., La Montanara, P., Cosentino, L., Lacivita, E., Leopoldo, M., Amendola, E., Gross, C., Landsberger, N. (2019) Rescue of prepulse inhibition deficit and brain mitochondrial dysfunction by pharmacological stimulation of the central serotonin receptor 7 in a mouse model of CDKL5 Deficiency Disorder. Neuropharmacology 144, 104– 114,  DOI: 10.1016/j.neuropharm.2018.10.018
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      23
      Rescue of prepulse inhibition deficit and brain mitochondrial dysfunction by pharmacological stimulation of the central serotonin receptor 7 in a mouse model of CDKL5 Deficiency Disorder
      Vigli, Daniele; Rusconi, Laura; Valenti, Daniela; La Montanara, Paolo; Cosentino, Livia; Lacivita, Enza; Leopoldo, Marcello; Amendola, Elena; Gross, Cornelius; Landsberger, Nicoletta; Laviola, Giovanni; Kilstrup-Nielsen, Charlotte; Vacca, Rosa A.; De Filippis, Bianca
      Neuropharmacology (2019), 144 (), 104-114CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)
      Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause CDKL5 Deficiency Disorder (CDD), a rare neurodevelopmental syndrome characterized by severe behavioral and physiol. symptoms. No cure is available for CDD. CDKL5 is a kinase that is abundantly expressed in the brain and plays a crit. role in neurodevelopmental processes, such as neuronal morphogenesis and plasticity. This study provides the first characterization of the neurobehavioural phenotype of 1 yr old Cdkl5-null mice and demonstrates that stimulation of the serotonin receptor 7 (5-HT7R) with the agonist mol. LP-211 (0.25 mg/kg once/day for 7 days) partially rescues the abnormal phenotype and brain mol. alterations in Cdkl5-null male mice. In particular, LP-211 treatment completely normalizes the prepulse inhibition defects obsd. in Cdkl5-null mice and, at a mol. level, restores the abnormal cortical phosphorylation of rpS6, a downstream target of mTOR and S6 kinase, which plays a direct role in regulating protein synthesis. Moreover, we demonstrate for the first time that mitochondria show prominent functional abnormalities in Cdkl5-null mouse brains that can be restored by pharmacol. stimulation of brain 5-HT7R.
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    24. 24
      Kroeze, W. K., Hufeisen, S. J., Popadak, B. A., Renock, S. M., Steinberg, S., Ernsberger, P., Jayathilake, K., Meltzer, H. Y., and Roth, B. L. (2003) H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology 28, 519– 526,  DOI: 10.1038/sj.npp.1300027
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      24
      H1-Histamine Receptor Affinity Predicts Short-Term Weight Gain for Typical and Atypical Antipsychotic Drugs
      Kroeze, Wesley K.; Hufeisen, Sandra J.; Popadak, Beth A.; Renock, Sean M.; Steinberg, SeAnna; Ernsberger, Paul; Jayathilake, Karu; Meltzer, Herbert Y.; Roth, Bryan L.
      Neuropsychopharmacology (2003), 28 (3), 519-526CODEN: NEROEW; ISSN:0893-133X. (Nature Publishing Group)
      As a result of superior efficacy and overall tolerability, atypical antipsychotic drugs have become the treatment of choice for schizophrenia and related disorders, despite their side effects. Wt. gain is a common and potentially serious complication of some antipsychotic drug therapy, and may be accompanied by hyperlipidemia, hypertension and hyperglycemia and, in some extreme cases, diabetic ketoacidosis. The mol. mechanism(s) responsible for antipsychotic drug-induced wt. gain are unknown, but have been hypothesized to be because of interactions of antipsychotic drugs with several neurotransmitter receptors, including 5-HT2A and 5-HT2C serotonin receptors, H1-histamine receptors, α1- and α2-adrenergic receptors, and m3-muscarinic receptors. To det. the receptor(s) likely to be responsible for antipsychotic-drug-induced wt. gain, we screened 17 typical and atypical antipsychotic drugs for binding to 12 neurotransmitter receptors. H1-histamine receptor affinities for this group of typical and atypical antipsychotic drugs were significantly correlated with wt. gain (Spearman ρ=-0.72; p∼0.01), as were affinities for α1A adrenergic (ρ=-0.54; p∼0.05), 5-HT2C (ρ=-0.49; p∼0.05) and 5-HT6 receptors (ρ=-0.54; p∼0.05), whereas eight other receptors' affinities were not. A principal components anal. showed that affinities at the H1, α2A, α2B, 5-HT2A, 5-HT2C, and 5-HT6 receptors were most highly correlated with the first principal component, and affinities for the D2, 5-HT1A, and 5-HT7 receptors were most highly correlated with the second principal component. A discriminant functions anal. showed that affinities for the H1 and α1A receptors were most highly correlated with the discriminant function axis. The discriminant function anal., as well as the affinity for the H1-histamine receptor alone, correctly classified 15 of the 17 drugs into two groups; those that induce wt. gain and those that do not. Because centrally acting H1-histamine receptor antagonists are known to induce wt. gain with chronic use, and because H1-histamine receptor affinities are pos. correlated with wt. gain among typical and atypical antipsychotic drugs, it is recommended that the next generation of atypical antipsychotic drugs be screened to avoid H1-histamine receptors.
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    25. 25
      Witt, N. A., Lee, B., Ghent, K., Zhang, W. Q., Pehrson, A. L., Sánchez, C., and Gould, G. G. (2019) Vortioxetine reduces marble burying but only transiently enhances social interaction preference in adult male BTBR T+Itpr3tf/J mice. ACS Chem. Neurosci. 10, 4319– 4327,  DOI: 10.1021/acschemneuro.9b00386
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      25
      Vortioxetine Reduces Marble Burying but Only Transiently Enhances Social Interaction Preference in Adult Male BTBR T+Itpr3tf/J Mice
      Witt, Nasriya A.; Lee, Benita; Ghent, Kaylee; Zhang, Wynne Q.; Pehrson, Alan L.; Sanchez, Connie; Gould, Georgianna G.
      ACS Chemical Neuroscience (2019), 10 (10), 4319-4327CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
      Vortioxetine is a multi-modal antidepressant with agonist activity at serotonin (5-HT)1A and 5-HT1B receptors that blocks the 5-HT transporter (SERT). Previously in male BTBR T+Itpr3tf/J (BTBR) mice the 5-HT1A agonist buspirone and SERT blocker fluoxetine enhanced social interaction but didn't reduce marble burying. We hypothesized vortioxetine, through SERT and 5-HT1A could improve BTBR sociability, and via 5-HT1B could reduce burying better than a selective SERT blocker. Vortioxetine (5-10 mg/kg) or sertraline (2 mg/kg) were administered 50 min pre-sociability and 75 min pre-marble burying tests. Vortioxetine (10 mg/kg) occupancy (%) was 84±1 for SERT, 31±12 for 5-HT1A and 80±5 for 5-HT1B in brain at 110 min post-injection, and serum oxytocin was 24% lower (p < 0.01) in vortioxetine-treated mice. Vortioxetine enhanced social sniffing, whereas sertraline enhanced overall sociability. However, the vortioxetine-induced increase in social sniffing was transient, as it was lost with 30-60 min pre-test delays in subsequent expts. Vortioxetine, and sertraline reduced BTBR marble burying. Based on vortioxetine occupancy SERT and/or 5-HT1B are more likely to underlie these effects than 5-HT1A occupancy. Overall, vortioxetine has great potential for suppressing restrictive-repetitive behaviors, but appears less promising as a sociability enhancer.
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    26. 26
      Canal, C. E., Felsing, D. E., Liu, Y., Zhu, W., Wood, J. T., Perry, C. K., Vemula, R., and Booth, R. G. (2015) An orally active phenylaminotetralin-chemotype serotonin 5-HT7 and 5-HT1A receptor partial agonist that corrects motor stereotypy in mouse models. ACS Chem. Neurosci. 6, 1259– 1270,  DOI: 10.1021/acschemneuro.5b00099
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      26
      An Orally Active Phenylaminotetralin-Chemotype Serotonin 5-HT7 and 5-HT1A Receptor Partial Agonist That Corrects Motor Stereotypy in Mouse Models
      Canal, Clinton E.; Felsing, Daniel E.; Liu, Yue; Zhu, Wanying; Wood, JodiAnne T.; Perry, Charles K.; Vemula, Rajender; Booth, Raymond G.
      ACS Chemical Neuroscience (2015), 6 (7), 1259-1270CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
      Stereotypy (e.g., repetitive hand waving) is a key phenotype of autism spectrum disorder, Fragile X and Rett syndromes, and other neuropsychiatric disorders, and its severity correlates with cognitive and attention deficits. There are no effective treatments, however, for stereotypy. Perturbation of serotonin (5-HT) neurotransmission contributes to stereotypy, suggesting that distinct 5-HT receptors may be pharmacotherapeutic targets to treat stereotypy and related neuropsychiatric symptoms. For example, preclin. studies indicate that 5-HT7 receptor activation corrects deficits in mouse models of Fragile X and Rett syndromes, and clin. trials for autism are underway with buspirone, a 5-HT1A partial agonist with relevant affinity at 5-HT7 receptors. Herein, we report the synthesis, in vitro mol. pharmacol., behavioral pharmacol., and pharmacokinetic parameters in mice after s.c. and oral administration of (+)-5-(2'-fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine ((+)-5-FPT), a new, dual partial agonist targeting both 5-HT7 (Ki = 5.8 nM, EC50 = 34 nM) and 5-HT1A (Ki = 22 nM, EC50 = 40 nM) receptors. Three unique, heterogeneous mouse models were used to assess the efficacy of (+)-5-FPT to reduce stereotypy: idiopathic jumping in C58/J mice, repetitive body rotations in C57BL/6J mice treated with the NMDA antagonist, MK-801, and repetitive head twitching in C57BL/6J mice treated with the 5-HT2 agonist, DOI. Systemic (+)-5-FPT potently and efficaciously reduced or eliminated stereotypy in each of the mouse models without altering locomotor behavior on its own, and addnl. tests showed that (+)-5-FPT, at the highest behaviorally active dose tested, enhanced social interaction and did not cause behaviors indicative of serotonin syndrome. These data suggest that (+)-5-FPT is a promising medication for treating stereotypy in psychiatric disorders.
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    27. 27
      Armstrong, J. L., Casey, A. B., Saraf, T. S., Mukherjee, M., Booth, R. G., and Canal, C. E. (2020) (S)-5-(2′-Fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine, a serotonin receptor modulator, possesses anticonvulsant, prosocial, and anxiolytic-like properties in an Fmr1 knockout mouse model of fragile X syndrome and autism spectrum disorder. ACS Pharmacol. Transl. Sci. 3, 509– 523,  DOI: 10.1021/acsptsci.9b00101
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      27
      (S)-5-(2'-Fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine, a Serotonin Receptor Modulator, Possesses Anticonvulsant, Prosocial, and Anxiolytic-like Properties in an Fmr1 Knockout Mouse Model of Fragile X Syndrome and Autism Spectrum Disorder
      Armstrong, Jessica L.; Casey, Austen B.; Saraf, Tanishka S.; Mukherjee, Munmun; Booth, Raymond G.; Canal, Clinton E.
      ACS Pharmacology & Translational Science (2020), 3 (3), 509-523CODEN: APTSFN; ISSN:2575-9108. (American Chemical Society)
      Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by intellectual disabilities and a plethora of neuropsychiatric symptoms. FXS is the leading monogenic cause of autism spectrum disorder (ASD), which is defined clin. by repetitive and/or restrictive patterns of behavior and social communication deficits. Epilepsy and anxiety are also common in FXS and ASD. Serotonergic neurons directly innervate and modulate the activity of neurobiol. circuits altered in both disorders, providing a rationale for investigating serotonin receptors (5-HTRs) as targets for FXS and ASD drug discovery. Previously we unveiled an orally active aminotetralin, (S)-5-(2'-fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (FPT), that exhibits partial agonist activity at 5-HT1ARs, 5-HT2CRs, and 5-HT7Rs and that reduces repetitive behaviors and increases social approach behavior in wild-type mice. Here we report that in an Fmr1 knockout mouse model of FXS and ASD, FPT is prophylactic for audiogenic seizures. No FPT-treated mice displayed audiogenic seizures, compared to 73% of vehicle-treated mice. FPT also exhibits anxiolytic-like effects in several assays and increases social interactions in both Fmr1 knockout and wild-type mice. Furthermore, FPT increases c-Fos expression in the basolateral amygdala, which is a preclin. effect produced by anxiolytic medications. Receptor pharmacol. assays show that FPT binds competitively and possesses rapid assocn. and dissocn. kinetics at 5-HT1ARs and 5-HT7Rs, yet has slow assocn. and rapid dissocn. kinetics at 5-HT2CRs. Finally, we reassessed and report FPT's affinity and function at 5-HT1ARs, 5-HT2CRs, and 5-HT7Rs. Collectively, these observations provide mounting support for further development of FPT as a pharmacotherapy for common neuropsychiatric symptoms in FXS and ASD.
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    28. 28
      Hedlund, P. B., Leopoldo, M., Caccia, S., Sarkisyan, G., Fracasso, C., Martelli, G., Lacivita, E., Berardi, F., and Perrone, R. (2010) LP-211 is a brain penetrant selective agonist for the serotonin 5-HT7 receptor. Neurosci. Lett. 481, 12– 16,  DOI: 10.1016/j.neulet.2010.06.036
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      28
      LP-211 is a brain penetrant selective agonist for the serotonin 5-HT7 receptor
      Hedlund, Peter B.; Leopoldo, Marcello; Caccia, Silvio; Sarkisyan, Gor; Fracasso, Claudia; Martelli, Giuliana; Lacivita, Enza; Berardi, Francesco; Perrone, Roberto
      Neuroscience Letters (2010), 481 (1), 12-16CODEN: NELED5; ISSN:0304-3940. (Elsevier Ireland Ltd.)
      We have detd. the pharmacol. profile of the new serotonin 5-HT7 receptor agonist N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (LP-211). Radioligand binding assays were performed on a panel of 5-HT receptor subtypes. The compd. was also evaluated in vivo by examg. its effect on body temp. regulation in mice lacking the 5-HT7 receptor (5-HT7 -/-) and their 5-HT7 +/+ sibling controls. Disposition studies were performed in mice of both genotypes. It was found that LP-211 was brain penetrant and underwent metabolic degrdn. to 1-(2-diphenyl)piperazine (RA-7). In vitro binding assays revealed that RA-7 possessed higher 5-HT7 receptor affinity than LP-211 and a better selectivity profile over a panel of 5-HT receptor subtypes. In vivo it was demonstrated that LP-211, and to a lesser degree RA-7, induced hypothermia in 5-HT7 +/+ but not in 5-HT7 -/- mice. Our results suggest that LP-211 can be used as a 5-HT7 receptor agonist in vivo.
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    29. 29
      Leopoldo, M., Lacivita, E., Contino, M., Colabufo, N. A., Berardi, F., and Perrone, R. (2007) Structure-activity relationship study on N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinehexanamides, a class of 5-HT7 receptor agents. 2. J. Med. Chem. 50, 4214– 4221,  DOI: 10.1021/jm070487n
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      29
      Structure-Activity Relationship Study on N-(1,2,3,4-Tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinehexanamides, a Class of 5-HT7 Receptor Agents. 2
      Leopoldo, Marcello; Lacivita, Enza; Contino, Marialessandra; Colabufo, Nicola A.; Berardi, Francesco; Perrone, Roberto
      Journal of Medicinal Chemistry (2007), 50 (17), 4214-4221CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Here the authors report the synthesis of N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinehexanamides 16-29 that were designed to elucidate both structure-affinity and -activity relations for the 5-HT7 receptor, by targeting the substituent in 2-position of the aryl linked to the piperazine ring. The affinities of 16-29 for 5-HT7, 5-HT1A, 5-HT2A, and D2 receptors were assessed by radioligand binding assays. The intrinsic activities at the 5-HT7 receptor of the most potent compds. were detd. Substituents covering a wide range of electronic, steric, and polar properties were evaluated, revealing a key role on 5-HT7 receptor affinity and intrinsic activity. Certain lipophilic substituents (SCH3, CHMe2, NMe2, CH3, Ph) led to high-affinity agonists, whereas OH and NHCH3 substituents switched intrinsic activity toward antagonism. 4-[2-(1-Methylethyl)phenyl]-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (19), 4-(2-diphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (21), and 4-(2-dimethylaminophenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (22) were identified as potent 5-HT7 receptor agonists (Ki = 0.13-1.1 nM, EC50 = 0.90-1.77 μM), showing selectivity over 5-HT1A, 5-HT2A, and D2 receptors.
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    30. 30
      Salerno, L., Pittalà, V., Modica, M. N., Siracusa, M. A., Intagliata, S., Cagnotto, A., Salmona, M., Kurczab, R., Bojarski, A. J., and Romeo, G. (2014) Structure-activity relationships and molecular modeling studies of novel arylpiperazinylalkyl 2-benzoxazolones and 2-benzothiazolones as 5-HT7 and 5-HT1A receptor ligands. Eur. J. Med. Chem. 85, 716– 726,  DOI: 10.1016/j.ejmech.2014.08.023
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      30
      Structure-activity relationships and molecular modeling studies of novel arylpiperazinylalkyl 2-benzoxazolones and 2-benzothiazolones as 5-HT7 and 5-HT1A receptor ligands
      Salerno, Loredana; Pittala, Valeria; Modica, Maria N.; Siracusa, Maria A.; Intagliata, Sebastiano; Cagnotto, Alfredo; Salmona, Mario; Kurczab, Rafal; Bojarski, Andrzej J.; Romeo, Giuseppe
      European Journal of Medicinal Chemistry (2014), 85 (), 716-726CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
      A novel series of arylpiperazinylalkyl 2-benzoxazolones and 2-benzothiazolones I (X = O, S; n = 4-7; R = C6H5, 2-OMeC6H4, 2-MeC6H4, CH2C6H5, 4-ClC6H4, 3-ClC6H4) was designed, synthesized and tested to evaluate their affinity for the 5-HT7 and 5-HT1A receptors. Compds. with a 2-benzothiazolone nucleus generally had affinity values higher than the corresponding 2-benzoxazolone compds. In particular, derivs. possessing a six or seven carbon chain linker between 2-benzothiazolone and arylpiperazine had Ki values in the subnanomolar range for the 5-HT1A receptor and in the low nanomolar range for the 5-HT7 receptor, indicating that they may be interesting dual ligands. Mol. modeling studies revealed different docking poses for the studied compds. in homol. models of 5-HT1A and 5-HT7 receptors, which explained their exptl. detd. affinities and general low selectivity. Addnl., structural interaction fingerprints anal. identified the important amino acid residues for the specific interactions of long-chain arylpiperazines within the binding pockets of both serotonin receptors.
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    31. 31
      Zajdel, P., Kos, T., Marciniec, K., Satała, G., Canale, V., Kamiński, K., Hołuj, M., Lenda, T., Koralewski, R., Bednarski, M. (2018) Novel multi-target azinesulfonamides of cyclic amine derivatives as potential antipsychotics with pro-social and pro-cognitive effects. Eur. J. Med. Chem. 145, 790– 804,  DOI: 10.1016/j.ejmech.2018.01.002
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      31
      Novel multi-target azinesulfonamides of cyclic amine derivatives as potential antipsychotics with pro-social and pro-cognitive effects
      Zajdel, Pawel; Kos, Tomasz; Marciniec, Krzysztof; Satala, Grzegorz; Canale, Vittorio; Kaminski, Krzysztof; Holuj, Malgorzata; Lenda, Tomasz; Koralewski, Robert; Bednarski, Marek; Nowinski, Leszek; Wojcikowski, Jacek; Daniel, Wladyslawa A.; Nikiforuk, Agnieszka; Nalepa, Irena; Chmielarz, Piotr; Kusmierczyk, Justyna; Bojarski, Andrzej J.; Popik, Piotr
      European Journal of Medicinal Chemistry (2018), 145 (), 790-804CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
      Currently used antipsychotics are characterized by multireceptor mode of action. While antagonism of dopamine D2 receptors is responsible for the alleviation of "pos." symptoms of schizophrenia and the effects at other, particularly serotonergic receptors are necessary for their addnl. therapeutic effects, there is no consensus regarding an "ideal" target engagement. Here, a detailed SAR anal. in a series of 45 novel azinesulfonamides of cyclic amine derivs., involving the aryl-piperazine/piperidine pharmacophore, central alicyclic amine and azinesulfonamide groups has led to the selection of (S)-4-((2-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)pyrrolidin-1-yl)sulfonyl)isoquinoline (62). The polypharmacol. profile of 62, characterized by partial 5-HT1AR agonism, 5-HT2A/5-HT7/D2/D3R antagonism, and blockade of SERT, reduced the "pos."-like, and "neg."-like symptoms of psychoses. Compd. 62 produced no catalepsy, demonstrated a low hyperprolactinemia liability and displayed pro-cognitive effects in the novel object recognition task and attentional set-shifting test. While assocn. of in vitro features with the promising in vivo profile of 62 is still not fully established, its clin. efficacy should be verified in further stages of development.
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    32. 32
      Lacivita, E., Podlewska, S., Speranza, L., Niso, M., Satała, G., Perrone, R., Perrone-Capano, C., Bojarski, A. J., and Leopoldo, M. (2016) Structural modifications of the serotonin 5-HT7 receptor agonist N-(4-cyanophenylmethyl)-4-(2-biphenyl)-1-piperazinehexanamide (LP-211) to improve in vitro microsomal stability: a case study. Eur. J. Med. Chem. 120, 363– 379,  DOI: 10.1016/j.ejmech.2016.05.005
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      32
      Structural modifications of the serotonin 5-HT7 receptor agonist N-(4-cyanophenylmethyl)-4-(2-biphenyl)-1-piperazinehexanamide (LP-211) to improve in vitro microsomal stability: A case study
      Lacivita, Enza; Podlewska, Sabina; Speranza, Luisa; Niso, Mauro; Satala, Grzegorz; Perrone, Roberto; Perrone-Capano, Carla; Bojarski, Andrzej J.; Leopoldo, Marcello
      European Journal of Medicinal Chemistry (2016), 120 (), 363-379CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
      The synthesis of thirty long-chain arylpiperazine, e.g., I analogs of the selective and brain penetrant 5-HT7 receptor agonist LP-211 designed to enhance stability towards microsomal oxidative metab is performed. Commonly used medicinal chem. strategies were used (i.e., redn. of overall lipophilicity, introduction of electron-withdrawing groups, blocking of potential vulnerable sites of metab.), and in vitro microsomal stability was tested. The data shows that the adopted design strategy does not directly translate into improvements in stability. Instead, the metabolic stability of the compds. was related to the presence of specific substituents in well-defined regions of the mol. The collected data allowed for the construction of a machine learning model that, in a given chem. space, is able to describe and quant. predict the metabolic stability of the compds. The majority of the synthesized compds. maintained high affinity for 5-HT7 receptors and showed selectivity towards 5-HT6 and dopamine D2 receptors and different selectivity for 5-HT1A and α1 adrenergic receptors. Compd. N-(4-cyanophenylmethyl)-4-[2-(4-methoxyphenyl)-4-fluorophenyl]-1-piperazinehexanamide showed 3-fold higher in vitro stability towards oxidative metab. than LP-211 and was able to stimulate neurite outgrowth in neuronal primary cultures through the 5-HT7 receptor in a shorter time and at a lower concn. than the agonist LP-211. A preliminary disposition study in mice revealed that compd. N-(4-cyanophenylmethyl)-4-[2-(4-methoxyphenyl)-4-fluorophenyl]-1-piperazinehexanamide was metabolically stable and was able to pass the blood-brain barrier, thus representing a new tool for studying the pharmacotherapeutic potential of 5-HT7 receptor in vivo.
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    33. 33
      Forster, E. A., Cliffe, I. A., Bill, D. J., Dover, G. M., Jones, D., Reilly, Y., and Fletcher, A. (1995) A pharmacological profile of the selective silent 5-HT1A receptor antagonist, WAY-100635. Eur. J. Pharmacol. 281, 81– 88,  DOI: 10.1016/0014-2999(95)00234-C
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      A pharmacological profile of the selective silent 5-HT1A receptor antagonist, WAY-100635
      Forster, Elaine A.; Cliffe, Ian A.; Bill, David J.; Dover, Gillian M.; Jones, Deborah; Reilly, Yvonne; Fletcher, Allan
      European Journal of Pharmacology (1995), 281 (1), 81-8CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier)
      WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohex anecarboxamide trihydrochloride) is an achiral phenylpiperazine deriv. that binds with high affinity and selectivity to the 5-HT1A receptor. WAY-100635 displaced specific binding of the 5-HT1A radioligand, [3H]8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), to rat hippocampal membranes with a pIC50 of 8.87. This represented a greater than 100-fold selectivity relative to binding at other 5-HT receptor subtypes and major neurotransmitter receptor, reuptake and ion channel sites. In functional assays, WAY-100635 was a potent 5-HT1A receptor antagonist, with no evidence of any 5-HT1A receptor agonist or partial agonist activity. In the isolated guinea-pig ileum WAY-100635 was a potent and, at high concns., an insurmountable antagonist of the 5-HT1A receptor agonist action of 5-carboxamidotryptamine, with an apparent pA2 value (at 0.3 nM) of 9.71. WAY-100635 blocked the inhibitory action of 8-OH-DPAT on dorsal raphe neuronal firing in the anesthetized rat at doses which had no inhibitory action per se. In behavioral models, WAY-100635 itself induced no overt behavioral changes but potently antagonized the behavioral syndrome induced by 8-OH-DPAT in the rat and guinea-pig (min. ED = 0.003 mg/kg s.c. and ID50 = 0.01 mg/kg s.c., resp.). WAY-100635 also blocked the hypothermia induced by 8-OH-DPAT in the mouse and rat with ID50 values of 0.01 mg/kg s.c. These data indicate that WAY-100635 will be used as a std. antagonist in further studies of 5-HT1A receptor function.
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    34. 34
      Bojarski, A. J., Paluchowska, M. H., Duszyńska, B., Bugno, R., Kłodzińska, A., Tatarczyńska, E., and Chojnacka-Wójcik, E. (2006) Structure-intrinsic activity relationship studies in the group of 1-imido/amido substituted 4-(4-arylpiperazin-1-yl)cyclohexane derivatives; new, potent 5-HT1A receptor agents with anxiolytic- like activity. Bioorg. Med. Chem. 14, 1391– 1402,  DOI: 10.1016/j.bmc.2005.09.060
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      Structure-intrinsic activity relationship studies in the group of 1-imido/amido substituted 4-(4-arylpiperazin-1-yl)cyclohexane derivatives; new, potent 5-HT1A receptor agents with anxiolytic- like activity
      Bojarski, Andrzej J.; Paluchowska, Maria H.; Duszynska, Beata; Bugno, Ryszard; Klodzinska, Aleksandra; Tatarczynska, Ewa; Chojnacka-Wojcik, Ewa
      Bioorganic & Medicinal Chemistry (2006), 14 (5), 1391-1402CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
      Introduction of 1,4-disubstituted cyclohexane ring in the structure of flexible long chain arylpiperazines resulted in linearly constrained, potent serotonin (5-HT)1A ligands. In order to trace structure-intrinsic activity relationships in this group, a new series of 1-substituted 4-(4-arylpiperazin-1-yl)cyclohexane derivs. with different cyclic imide/amide termini, and their flexible, tetramethylene analogs were synthesized and pharmacol. evaluated for 5-HT1A receptors. In vitro binding expts. revealed that all the compds. were potent 5-HT1A receptor agents (K i = 1.9-74 nM). Some derivs. tested addnl. showed also high affinity for α1-adrenergic receptors (K i = 2.9-101 nM) and for 5-HT7 receptors. Functional in vivo examn. revealed that rigid ligands with o-OCH3 group in the aryl moiety and cyclic imide system in the opposite terminal behaved like postsynaptic 5-HT1A receptor antagonists. On the other hand, unsubstituted, m-Cl, or m-CF3 substituted derivs. as well as those with cyclic amide group in the terminal fragment exhibited agonistic or partial agonistic activity. Three out of four derivs. tested, i.e., postsynaptic 5-HT1A antagonists 9 and 10, and partial agonist 16, showed anxiolytic-like activity in the conflict drinking (Vogel) test in rats.
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    35. 35
      Kumar, J. S., Prabhakaran, J., Majo, V. J., Milak, M. S., Hsiung, S. C., Tamir, H., Simpson, N. R., Van Heertum, R. L., Mann, J. J., and Parsey, R. V. (2007) Synthesis and in vivo evaluation of a novel 5-HT1A receptor agonist radioligand (O-methyl- 11C]2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione in nonhuman primates. Eur. J. Nucl. Med. Mol. Imaging 34, 1050– 1060,  DOI: 10.1007/s00259-006-0324-y
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      Synthesis and in vivo evaluation of a novel 5-HT1A receptor agonist radioligand [O-methyl-11C]2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione in nonhuman primates
      Kumar, J. S. Dileep; Prabhakaran, Jaya; Majo, Vattoly J.; Milak, Matthew S.; Hsiung, Shu-Chi; Tamir, Hadassah; Simpson, Norman R.; Van Heertum, Ronald L.; Mann, J. John; Parsey, Ramin V.
      European Journal of Nuclear Medicine and Molecular Imaging (2007), 34 (7), 1050-1060CODEN: EJNMA6; ISSN:1619-7070. (Springer)
      Purpose: Serotonin1A (5-HT1A) receptors exist in high- and low-affinity states, and agonist ligands bind preferentially to the high-affinity state of the receptor and provide a measure of functional 5-HT1A receptors. Although the antagonist tracers are established PET ligands in clin. studies, a successful 5-HT1A receptor agonist radiotracer in living brain has not been reported. [11C]MPT, our first-generation agonist radiotracer, shows in vivo specificity in baboons; however, its utility is limited owing to slow washout and immeasurable plasma free fraction. Hence we performed structure-activity relationship studies of MPT to optimize a radiotracer that will permit valid quantification of 5-HT1A receptor binding. We now report the synthesis and evaluation of [11C]MMP as an agonist PET tracer for 5-HT1A receptors in baboons. Methods: In vitro binding assays were performed in bovine hippocampal membranes and membranes of CHO cells expressing 5-HT1A receptors. [11C] labeling of MMP was performed by reacting desmethyl-MMP with [11C]CH3OTf. In vivo studies were performed in baboons, and blocking studies were conducted by pretreatment with 5-HT1A receptor ligands WAY-100635 and (±)-8-OH-DPAT. Results: MMP is a selective 5-HT1A receptor agonist (Ki 0.15 nM). Radiosynthesis of [11C]MMP was achieved in 30 ± 5% (n = 15) yield at EOS with a specific activity of 2,600 ± 500 Ci/mmol (n = 12). PET studies in baboons demonstrated specific binding of [11C]MMP to 5-HT1A receptor-enriched brain regions, as confirmed by blockade with WAY-100635 and (±)-8-OH-DPAT. Conclusion: We identified [11C]MMP as an optimal agonist PET tracer that shows quantifiable, specific binding in vivo to 5-HT1A receptors in baboons.
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    36. 36
      López-Rodríguez, M. L., Morcillo, M. J., Fernández, E., Benhamú, B., Tejada, I., Ayala, D., Viso, A., Campillo, M., Pardo, L., Delgado, M. (2005) Synthesis and structure-activity relationships of a new model of arylpiperazines. 8. Computational simulation of ligand-receptor interaction of 5-HT1AR agonists with selectivity over alpha1-adrenoceptors. J. Med. Chem. 48, 2548– 2558,  DOI: 10.1021/jm048999e
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      Synthesis and Structure-Activity Relationships of a New Model of Arylpiperazines. 8.Computational Simulation of Ligand-Receptor Interaction of 5-HT1AR Agonists with Selectivity over α1-Adrenoceptors
      Lopez-Rodriguez, Maria L.; Morcillo, Maria Jose; Fernandez, Esther; Benhamu, Bellinda; Tejada, Ignacio; Ayala, David; Viso, Alma; Campillo, Mercedes; Pardo, Leonardo; Delgado, Mercedes; Manzanares, Jorge; Fuentes, Jose A.
      Journal of Medicinal Chemistry (2005), 48 (7), 2548-2558CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      We have designed and synthesized a new series of arylpiperazines V exhibiting high 5-HT1AR affinity and selectivity over α1-adrenoceptors. The new selective 5-HT1AR ligands contain a hydantoin (m = 0) or diketopiperazine (m = 1) moiety and an arylpiperazine moiety sepd. by one methylene unit (n = 1). The aryl substituent of the piperazine moiety (Ar) consists of different benzofused rings mimicking the favorable voluminous substituents at ortho and meta positions predicted by 3D-QSAR anal. in the previously reported series. In particular, (S)-2-[[4-(naphth-1-yl)piperazin-1-yl]methyl]-1,4-dioxoperhydropyrrolo[1,2-a]pyrazine [CSP-2503] (5-HT1A, Ki = 4.1 nM; α1, Ki > 1000 nM) has been pharmacol. characterized as a 5-HT1AR agonist at somatodendritic and postsynaptic sites, endowed with anxiolytic properties. CSP-2503 is predicted, in computer simulations, to bind Asp3.32 in TMH 3, Thr5.39 and Ser5.42 in TMH 5, and Trp6.48 in TMH 6. We propose that agonists modify, by means of an explicit hydrogen bond, the conformation of Trp6.48 from pointing toward TMH 7, in the inactive gauche+ conformation, to pointing toward the ligand binding site, in the active trans conformation.
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    37. 37
      Cantillon, M., Prakash, A., Alexander, A., Ings, R., Sweitzer, D., and Bhat, L. (2017) Dopamine serotonin stabilizer RP5063: a randomized, double-blind, placebo-controlled multicenter trial of safety and efficacy in exacerbation of schizophrenia or schizoaffective disorder. Schizophr. Res. 189, 126– 133,  DOI: 10.1016/j.schres.2017.01.043
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      Dopamine serotonin stabilizer RP5063: A randomized, double-blind, placebo-controlled multicenter trial of safety and efficacy in exacerbation of schizophrenia or schizoaffective disorder
      Cantillon Marc; Prakash Arul; Alexander Ajay; Ings Robert; Sweitzer Dennis; Bhat Laxminarayan
      Schizophrenia research (2017), 189 (), 126-133 ISSN:.
      The study objectives were to evaluate the efficacy, safety, tolerability, and pharmacokinetics of RP5063 versus placebo. The study was conducted in adults with acute exacerbation of schizophrenia or schizoaffective disorder. This 28-day, multicenter, placebo-controlled, double-blind study randomized 234 subjects to RP5063 15, 30, or 50mg; aripiprazole; or placebo (3:3:3:1:2) once daily. The aripiprazole arm was included solely to show assay sensitivity and was not powered to show efficacy. The primary endpoint was change from baseline to Day 28/EOT (End-of-Treatment) in Positive and Negative Syndrome Scale (PANSS) total score; secondary endpoints included PANSS subscales, improvement ≥1 point on the Clinical Global Impressions-Severity (CGI-S), depression and cognition scales. The primary analysis of PANSS Total showed improvement by a mean (SE) of -20.23 (2.65), -15.42 (2.04), and -19.21 (2.39) in the RP5063 15, 30, and 50mg arms, versus -11.41 (3.45) in the placebo arm. The difference between treatment and placebo reached statistical significance for the 15mg (p=0.021) and 50mg (p=0.016) arms. Improvement with RP5063 was also seen for multiple secondary efficacy outcomes. Discontinuation for any reason was much lower for RP5063 (14%, 25%, 12%) versus placebo (26%) and aripiprazole (35%). The most common treatment-emergent adverse events (TEAE) in the RP5063 groups were insomnia and agitation. There were no significant changes in body weight, electrocardiogram, or incidence of orthostatic hypotension; there was a decrease in blood glucose, lipid profiles, and prolactin levels. In conclusion, the novel dopamine serotonin stabilizer, RP5063 is an efficacious and well-tolerated treatment for acute exacerbation of schizophrenia or schizoaffective disorder.
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    38. 38
      Chen, Y., Wang, S., Xu, X., Liu, X., Yu, M., Zhao, S., Liu, S., Qiu, Y., Zhang, T., Liu, B. F. (2013) Synthesis and biological investigation of coumarin piperazine (piperidine) derivatives as potential multireceptor atypical antipsychotics. J. Med. Chem. 56, 4671– 4690,  DOI: 10.1021/jm400408r
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      Synthesis and Biological Investigation of Coumarin Piperazine (Piperidine) Derivatives as Potential Multireceptor Atypical Antipsychotics
      Chen, Yin; Wang, Songlin; Xu, Xiangqing; Liu, Xin; Yu, Minquan; Zhao, Song; Liu, Shicheng; Qiu, Yinli; Zhang, Tan; Liu, Bi-Feng; Zhang, Guisen
      Journal of Medicinal Chemistry (2013), 56 (11), 4671-4690CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      The discovery and synthesis of potential and novel antipsychotic coumarin derivs., assocd. with potent dopamine D2, D3, and serotonin 5-HT1A and 5-HT2A receptor properties, are the focus of the present article. The most-promising deriv. was 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl)butoxy)-4-methyl-8-chloro-2H-chromen-2-one (I). This deriv. possesses unique pharmacol. features, including high affinity for dopamine D2 and D3 and serotonin 5-HT1A and 5-HT2A receptors. Moreover, it possesses low affinity for 5-HT2C and H1 receptors (to reduce the risk of obesity assocd. with chronic treatment) and hERG channels (to reduce the incidence of torsade de pointes). In animal models, compd. I inhibited apomorphine-induced climbing behavior, MK-801-induced hyperactivity, and the conditioned avoidance response without observable catalepsy at the highest dose tested. Further, fewer preclin. adverse events were noted with I compared with risperidone in assays that measured prolactin secretion and wt. gain. Acceptable pharmacokinetic properties were also noted with I. Taken together, I may constitute a novel class of drugs for the treatment of schizophrenia.
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      Bojarski, A. J. (2006) Pharmacophore models for metabotropic 5-HT receptor ligands. Curr. Top. Med. Chem. 6, 2005– 2026,  DOI: 10.2174/156802606778522186
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      Pharmacophore models for metabotropic 5-HT receptor ligands
      Bojarski, Andrzej J.
      Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2006), 6 (18), 2005-2026CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)
      A review. An overview of pharmacophore models, developed for different subtypes of serotonin receptors belonging to the GPCR family, is presented. Starting with early models for 5-HT1A and 5-HT2 receptor ligands, and ending with the latest ones for 5-HT6- and 5-HT7 receptors, as many as fifty others are briefly summarized. No models have been developed for 5-HT1F-, 5-HT2B- and 5-HT5B receptor ligands, and in the case of 5-HT1E- and 5-HT5ARs only single pilot studies with non-selective tryptamine derivs. are reported. For all the other subtypes of 5-HTRs, various pharmacophore hypotheses - either qual. and/or quant. - are characterized by sets of ligands used for their generation, a templates for alignment, the computational methods applied and, eventually, interfeature distances and/or statistical results - if available.
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      Wager, T. T., Hou, X., Verhoest, P. R., and Villalobos, A. (2016) Central Nervous System Multiparameter Optimization Desirability: application in drug discovery. ACS Chem. Neurosci. 7, 767– 775,  DOI: 10.1021/acschemneuro.6b00029
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      Central Nervous System Multiparameter Optimization Desirability: Application in Drug Discovery
      Wager, Travis T.; Hou, Xinjun; Verhoest, Patrick R.; Villalobos, Anabella
      ACS Chemical Neuroscience (2016), 7 (6), 767-775CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
      Significant progress has been made in prospectively designing mols. using the central nervous system multiparameter optimization (CNS MPO) desirability tool, as evidenced by the anal. reported herein of a second wave of drug candidates that originated after the development and implementation of this tool. This simple-to-use design algorithm has expanded design space for CNS candidates and has further demonstrated the advantages of utilizing a flexible, multiparameter approach in drug discovery rather than individual parameters and hard cutoffs of physicochem. properties. The CNS MPO tool has helped to increase the percentage of compds. nominated for clin. development that exhibit alignment of ADME attributes, cross the blood-brain barrier, and reside in lower-risk safety space (low ClogP and high TPSA). The use of this tool has played a role in reducing the no. of compds. submitted to exploratory toxicity studies and increasing the survival of our drug candidates through regulatory toxicol. into First in Human studies. Overall, the CNS MPO algorithm has helped to improve the prioritization of design ideas and the quality of the compds. nominated for clin. development.
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      Obach, R. S., Baxter, J. G., Liston, T. E., Silber, B. M., Jones, B. C., MacIntyre, F., Rance, D. J., and Wastall, P. (1997) The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data. J. Pharmacol. Exp. Ther. 283, 46– 58
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      The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data
      Obach, R. Scott; Baxter, James G.; Liston, Theodore E.; Silber, B. Michael; Jones, Barry C.; Macintyre, Flona; Rance, David J.; Wastall, Philip
      Journal of Pharmacology and Experimental Therapeutics (1997), 283 (1), 46-58CODEN: JPETAB; ISSN:0022-3565. (Williams & Wilkins)
      A review with 35 refs. We describe a comprehensive retrospective anal. in which the abilities of several methods by which human pharmacokinetic parameters are predicted from preclin. pharmacokinetic data and/or in vitro metab. data were assessed. The prediction methods examd. included both methods from the scientific literature as well as some described in this report for the first time. Four methods were examd. for their ability to predict human vol. of distribution. Three were highly predictive, yielding, on av., predictions that were within 60% to 90% of actual values. Twelve methods were assessed for their utility in predicting clearance. The most successful allometric scaling method yielded clearance predictions that were, on av., within 80% of actual values. The best methods in which in vitro metab. data from human liver microsomes were scaled to in vivo clearance values yielded predicted clearance values that were, on av., within 70% to 80% of actual values. Human t1/2 was predicted by combining predictions of human vol. of distribution and clearance. The best t1/2 prediction methods successfully assigned compds. to appropriate dosing regimen categories (e.g., once daily, twice daily and so forth) 70% to 80% of the time. In addn., correlations between human t1/2 and t1/2 values from preclin. species were also generally successful (72-87%) when used to predict human dosing regimens. In summary, this retrospective anal. has identified several approaches by which human pharmacokinetic data can be predicted from preclin. data. Such approaches should find utility in the drug discovery and development processes in the identification and selection of compds. that will possess appropriate pharmacokinetic characteristics in humans for progression to clin. trials.
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      Kumar, J. S., Majo, V. J., Hsiung, S. C., Millak, M. S., Liu, K. P., Tamir, H., Prabhakaran, J., Simpson, N. R., Van Heertum, R. L., Mann, J. J. (2006) Synthesis and in vivo validation of [O-methyl-11C]2-{4-[4-(7-methoxynaphthalen-1-yl)piperazin-1-yl]butyl}-4-methyl-2H-[1,2,4]triazine-3,5-dione: a novel 5-HT1A receptor agonist positron emission tomography ligand. J. Med. Chem. 49, 125– 134,  DOI: 10.1021/jm050725j
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      Synthesis and in Vivo Validation of [O-Methyl-11C]-2-[4-[4-(7-methoxy-1-naphthalenyl)-1-piperazinyl]butyl]-4-methyl-2H-[1,2,4]triazine-3,5-dione: A Novel 5-HT1A Receptor Agonist Positron Emission Tomography Ligand
      Kumar, J. S. Dileep; Majo, Vattoly J.; Hsiung, Shu-Chi; Millak, Matthew S.; Liu, Kuo-Peing; Tamir, Hadassah; Prabhakaran, Jaya; Simpson, Norman R.; Van Heertum, Ronald L.; Mann, J. John; Parsey, Ramin V.
      Journal of Medicinal Chemistry (2006), 49 (1), 125-134CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Antagonist 5-HT1A PET ligands are available, but an agonist ligand would give more information about signal transduction capacity. Synthesis and in vivo evaluation of [O-methyl-11C]2-{4-[4-(7-methoxy-1-naphthalenyl)-1-piperazinyl]butyl}-4-methyl-2H-[1,2,4]triazine-3,5-dione (I), a potential high affinity (Ki = 1.36 nM) 5-HT1A agonist PET tracer is described. Piperazine I is a 5-HT1A agonist with an EC50 comparable to serotonin, based on cAMP formation and GTPγS binding assays. Radiosynthesis of [11C]-I has been achieved by reacting 2-[4-[4-(7-hydroxy-1-naphthalenyl)-1-piperazinyl]butyl]-4-methyl-2H-[1,2,4]triazine-3,5-dione and [11C]CH3OTf in 25% (n = 15) yield at the end of synthesis (EOS). The chem. and radiochem. purity of [11C]-I were >99% with a specific activity 1500 Ci/mmol (n = 15). PET studies in anesthetized baboon demonstrate [11C]-I specific binding in brain regions rich in 5-HT1A receptors. Binding of [11C]-I was blocked by WAY100635 and 8-OH-DPAT. The regional brain vols. of distribution (VT) of [11C]-I in baboon correlate with [11C]WAY100635 VT in baboon monkeys. These data provide evidence that [11C]-I is the first promising agonist PET tracer for the 5-HT1A receptors.
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      Lacivita, E., Patarnello, D., Stroth, N., Caroli, A., Niso, M., Contino, M., De Giorgio, P., Di Pilato, P., Colabufo, N. A., Berardi, F. (2012) Investigations on the 1-(2-biphenyl)piperazine motif: identification of new potent and selective ligands for the serotonin7 (5-HT7) receptor with agonist or antagonist action in vitro or ex vivo. J. Med. Chem. 55, 6375– 6380,  DOI: 10.1021/jm3003679
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      Investigations on the 1-(2-Biphenyl)piperazine Motif: Identification of New Potent and Selective Ligands for the Serotonin7 (5-HT7) Receptor with Agonist or Antagonist Action in Vitro or ex Vivo
      Lacivita, Enza; Patarnello, Daniela; Stroth, Nikolas; Caroli, Antonia; Niso, Mauro; Contino, Marialessandra; De Giorgio, Paola; Di Pilato, Pantaleo; Colabufo, Nicola A.; Berardi, Francesco; Perrone, Roberto; Svenningsson, Per; Hedlund, Peter B.; Leopoldo, Marcello
      Journal of Medicinal Chemistry (2012), 55 (14), 6375-6380CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Herein the design, synthesis, and 5-HT7 receptor affinity of a set of 1-(3-biphenyl)- and 1-(2-biphenyl)piperazines are reported. The effect on 5-HT7 affinity of various substituents on the second (distal) Ph ring was analyzed. Several compds. showed 5-HT7 affinities in the nanomolar range and >100-fold selectivity over 5-HT1A and adrenergic α1 receptors. 1-[2-(4-Methoxyphenyl)phenyl]piperazine showed 5-HT7 agonist properties in a guinea pig ileum assay but blocked 5-HT-mediated cAMP accumulation in 5-HT7-expressing HeLa cells.
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    45. 45
      Elgogary, S. R., Hashem, N. M., and Khodeir, M. N. (2015) Synthesis and photooxygenation of linear and angular furocoumarin derivatives as a hydroxyl radical source: psoralen, pseudopsoralen, isopseudopsoralen, and allopsoralen. J. Heteroc. Chem. 52, 506– 512,  DOI: 10.1002/jhet.2084
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      Pendin, D., Norante, R., De Nadai, A., Gherardi, G., Vajente, N., Basso, E., Kaludercic, N., Mammucari, C., Paradisi, C., Pozzan, T. (2019) A synthetic fluorescent mitochondria-targeted sensor for ratiometric imaging of calcium in live cells. Angew. Chem., Int. Ed. 58, 9917– 9922,  DOI: 10.1002/anie.201902272
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      A Synthetic Fluorescent Mitochondria-Targeted Sensor for Ratiometric Imaging of Calcium in Live Cells
      Pendin, Diana; Norante, Rosa; De Nadai, Andrea; Gherardi, Gaia; Vajente, Nicola; Basso, Emy; Kaludercic, Nina; Mammucari, Cristina; Paradisi, Cristina; Pozzan, Tullio; Mattarei, Andrea
      Angewandte Chemie, International Edition (2019), 58 (29), 9917-9922CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Ca2+ handling by mitochondria is crucial for cell life and the direct measure of mitochondrial Ca2+ concn. in living cells is of pivotal interest. Genetically-encoded indicators greatly facilitated this task, however they require demanding delivery procedures. On the other hand, existing mitochondria-targeted synthetic Ca2+ indicators are plagued by several drawbacks, for example, non-specific localization, leakage, toxicity. Here we report the synthesis and characterization of a new fluorescent Ca2+ sensor, named mt-fura-2, obtained by coupling two triphenylphosphonium cations to the mol. backbone of the ratiometric Ca2+ indicator fura-2. Mt-fura-2 binds Ca2+ with a dissocn. const. of ≈1.5 μM in vitro. When loaded in different cell types as acetoxymethyl ester, the probe shows proper mitochondrial localization and accurately measures matrix [Ca2+] variations, proving its superiority over available dyes. We describe the synthesis, characterization and application of mt-fura-2 to cell types where the delivery of genetically-encoded indicators is troublesome.
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      Brown, J. W., Gangloff, A. R., Jennings, A. J., and Vu, P. H. (2010) Poly (ADP-Ribose) Polymerase (PARP) inhibitors, WO2010111626.
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      Kolyasnikova, K. N., Vichuzhanin, M. V., Konstantinopol’skii, M. A., Trofimov, S. S., and Gudasheva, T. A. (2012) Synthesis and pharmacological activity of analogs of the endogenous neuropeptide cycloprolylglycine. Pharm. Chem. J. 46, 96– 102,  DOI: 10.1007/s11094-012-0741-0
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      Kolyasnikova, K. N.; Vichuzhanin, M. V.; Konstantinopol'skii, M. A.; Trofimov, S. S.; Gudasheva, T. A.
      Pharmaceutical Chemistry Journal (2012), 46 (2), 96-102CODEN: PCJOAU; ISSN:0091-150X. (Springer)
      A series of analogs and homologs of the endogenous cyclic dipeptide cycloprolylglycine were synthesized. The nootropic properties of the synthesized compds. were investigated on an exptl. model of a passive avoidance test with electroshock- or scopolamine-induced amnesia. The anxiolytic activity was examd. by an elevated plus-maze test. It is established that the pharmacophores responsible for the nootropic and anxiolytic activities are different. Hypotheses concerning the structure of the binding regions with the corresponding pharmacol. targets are formulated.
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      Kaar, S. J., Natesan, S., McCutcheon, R., and Howes, O. D. (2020) Antipsychotics: mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology. Neuropharmacology 172, 107704,  DOI: 10.1016/j.neuropharm.2019.107704
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      Antipsychotics: Mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology
      Kaar, Stephen J.; Natesan, Sridhar; McCutcheon, Robert; Howes, Oliver D.
      Neuropharmacology (2020), 172 (), 107704CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)
      A review. Antipsychotic drugs are central to the treatment of schizophrenia and other psychotic disorders but are ineffective for some patients and assocd. with side-effects and nonadherence in others. We review the in vitro, pre-clin., clin. and mol. imaging evidence on the mode of action of antipsychotics and their side-effects. This identifies the key role of striatal dopamine D2 receptor blockade for clin. response, but also for endocrine and motor side-effects, indicating a therapeutic window for D2 blockade. We consider how partial D2/3 receptor agonists fit within this framework, and the role of off-target effects of antipsychotics, particularly at serotonergic, histaminergic, cholinergic, and adrenergic receptors for efficacy and side-effects such as wt. gain, sedation and dysphoria. We review the neurobiol. of schizophrenia relevant to the mode of action of antipsychotics, and for the identification of new treatment targets. This shows elevated striatal dopamine synthesis and release capacity in dorsal regions of the striatum underlies the pos. symptoms of psychosis and suggests reduced dopamine release in cortical regions contributes to cognitive and neg. symptoms. Current drugs act downstream of the major dopamine abnormalities in schizophrenia, and potentially worsen cortical dopamine function. We consider new approaches including targeting dopamine synthesis and storage, autoreceptors, and trace amine receptors, and the cannabinoid, muscarinic, GABAergic and glutamatergic regulation of dopamine neurons, as well as post-synaptic modulation through phosphodiesterase inhibitors. Finally, we consider treatments for cognitive and neg. symptoms such dopamine agonists, nicotinic agents and AMPA modulators before discussing immunol. approaches which may be disease modifying.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVWksLfI&md5=07d3f132f1614b03e3503f54c5aeb0fa
    51. 51
      Lacivita, E., Niso, M., Stama, M. L., Arzuaga, A., Altamura, C., Costa, L., Desaphy, J. F., Ragozzino, M. E., Ciranna, L., and Leopoldo, M. (2020) Privileged scaffold-based design to identify a novel drug-like 5-HT7 receptor-preferring agonist to target fragile X syndrome. Eur. J. Med. Chem. 199, 112395,  DOI: 10.1016/j.ejmech.2020.112395
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      Privileged scaffold-based design to identify a novel drug-like 5-HT7 receptor-preferring agonist to target Fragile X syndrome
      Lacivita, Enza; Niso, Mauro; Stama, Madia Letizia; Arzuaga, Anna; Altamura, Concetta; Costa, Lara; Desaphy, Jean-Francois; Ragozzino, Michael E.; Ciranna, Lucia; Leopoldo, Marcello
      European Journal of Medicinal Chemistry (2020), 199 (), 112395CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
      Recent preclin. studies have shown that activation of the serotonin 5-HT7 receptor has the potential to treat neurodevelopmental disorders such as Fragile X syndrome, a rare disease characterized by autistic features. With the aim to provide the scientific community with diversified drug-like 5-HT7 receptor-preferring agonists, we designed a set of new long-chain arylpiperazines by exploiting structural fragments present in clin. approved drugs or in preclin. candidates (privileged scaffolds). The new compds. were synthesized, tested for their affinity at 5-HT7 and 5-HT1A receptors, and screened for their in vitro stability to microsomal degrdn. and toxicity. Selected compds. were characterized as 5-HT7 receptor-preferring ligands, endowed with high metabolic stability and low toxicity. Compd. 7g emerged as a drug-like 5-HT7 receptor-preferring agonist capable to rescue synaptic plasticity and attenuate stereotyped behavior in a mouse model of Fragile X syndrome.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXpsl2qsrk%253D&md5=8d1ba083c6348813fb6119d2a15a64a4
    52. 52
      Di, L., Kerns, E. H., Ma, X. J., Huang, Y., and Carter, G. T. (2008) Applications of high throughput microsomal stability assay in drug discovery. Comb. Chem. High Throughput Screening 11, 469– 476,  DOI: 10.2174/138620708784911429
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      Applications of high throughput microsomal stability assay in drug discovery
      Di, Li; Kerns, Edward H.; Ma, Xuewen JoAnn; Huang, Youping; Carter, Guy T.
      Combinatorial Chemistry & High Throughput Screening (2008), 11 (6), 469-476CODEN: CCHSFU; ISSN:1386-2073. (Bentham Science Publishers Ltd.)
      High throughput in vitro microsomal stability assays are widely used in drug discovery as an indicator for in vivo stability, which affects pharmacokinetics. This is based on in-depth research involving a limited no. of model drug-like compds. that are cleared predominantly by cytochrome P 450 metab. However, drug discovery compds. are often not drug-like, are assessed with high throughput assays, and have many potential uncharacterized in vivo clearance mechanisms. Therefore, it is important to det. the correlation between high throughput in vitro microsomal stability data and abbreviated discovery in vivo pharmacokinetics study data for a set of drug discovery compds. to have evidence for how the in vitro assay can be reliably applied by discovery teams for making crit. decisions. In this study the relationship between in vitro single time point high throughput microsomal stability and in vivo clearance from abbreviated drug discovery pharmacokinetics studies was examd. using 306 real world drug discovery compds. The results showed that in vitro Phase I microsomal stability t1/2 is significantly correlated to in vivo clearance. For compds. with low in vitro rat microsomal stability (t1/2 < 15 min), 87% showed high clearance in vivo (CL > 25 mL/min/kg). This demonstrates that high throughput microsomal stability data are very effective in identifying compds. with significant clearance liabilities in vivo. For compds. with high in vitro rat microsomal stability (t1/2 > 15 min), no significant differentiation was obsd. between high and low clearance compds. This is likely owing to other clearance pathways, in addn. to cytochrome P 450 metab. that enhances in vivo clearance. This finding supports the strategy used by medicinal chemists and drug discovery teams of applying the in vitro data to triage compds. for in vivo PK and efficacy studies and guide structural modification to improve metabolic stability. When in vitro and in vivo data are both available for a compd., potential in vivo clearance pathways can be diagnosed to guide further discovery studies.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXnsVanurw%253D&md5=9ca4c9d4ab4fa48306ccb76ba486d815
    53. 53
      Guscott, M. R., Egan, E., Cook, G. P., Stanton, J. A., Beer, M. S., Rosahl, T. W., Hartmann, S., Kulagowski, J., McAllister, G., Fone, K. F. C. (2003) The hypothermic effect of 5-CT in mice is mediated through the 5-HT7 receptor. Neuropharmacology 44, 1031– 1037,  DOI: 10.1016/S0028-3908(03)00117-5
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      The hypothermic effect of 5-CT in mice is mediated through the 5-HT7 receptor
      Guscott, M. R.; Egan, E.; Cook, G. P.; Stanton, J. A.; Beer, M. S.; Rosahl, T. W.; Hartmann, S.; Kulagowski, J.; McAllister, G.; Fone, K. C. F.; Hutson, P. H.
      Neuropharmacology (2003), 44 (8), 1031-1037CODEN: NEPHBW; ISSN:0028-3908. (Elsevier Science Ltd.)
      The 5-HT7 receptor is a recent addn. to the 5-HT receptor family and to date there is no clear idea as to its potential role in the CNS. The receptor has been mapped by in situ hybridization and 5-HT7-like immunoreactivity and has been detected in discrete areas of the brain including the hypothalamus (Oliver et al., 1999). This suggests the receptor may be involved in temp. regulation and have shown that a selective 5-HT7 receptor antagonist reverses the hypothermic effect of 5-CT in guinea-pigs. The current study confirmed that the 5-HT7 receptor antagonists, SB-269970 (1-30 mg/kg, i.p.) and SB-258719 (5-20 mg/kg, i.p.), but not the 5-HT1A receptor antagonist, WAY 100635(0.1-1 mg/kg, s.c.), or the 5-HT1B/D antagonist, GR127935 (1.25-5 mg/kg, i.p.), reversed the hypothermic effect of 5-CT in mice. In addn. the effect of 5-CT on body temp. was examd. on 5-HT7 receptor null mutant mice. 5-CT (0.1-1 mg/kg, i.p.) significantly reduced rectal temp. in wild-type but not 5-HT7 receptor knockout mice. This suggests that the hypothermic effects of 5-CT are mediated through the 5-HT7 receptor. All procedures were carried out in accordance with the UK Animals (Scientific Procedures) Act (1986).
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXjvFeksLk%253D&md5=6ac84e94f9da78d01d657d059eea472d
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      Salonikidis, P. S., Zeug, A., Kobe, F., Ponimaskin, E., and Richter, D. W. (2008) Quantitative measurement of cAMP concentration using an exchange protein directly activated by a cAMP- based FRET-sensor. Biophys. J. 95, 5412– 5423,  DOI: 10.1529/biophysj.107.125666
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      Quantitative measurement of cAMP concentration using an exchange protein directly activated by a cAMP-based FRET-sensor
      Salonikidis, Petrus S.; Zeug, Andre; Kobe, Fritz; Ponimaskin, Evgeni; Richter, Diethelm W.
      Biophysical Journal (2008), 95 (11), 5412-5423CODEN: BIOJAU; ISSN:0006-3495. (Biophysical Society)
      Forster resonance energy transfer (FRET)-based biosensors for the quant. anal. of intracellular signaling, including sensors for monitoring cAMP, are of increasing interest. The measurement of the donor/acceptor emission ratio in tandem biosensors excited at the donor excitation wavelength is a commonly used technique. A general problem, however, is that this ratio varies not only with the changes in cAMP concn. but also with the changes of the ionic environment or other factors affecting the folding probability of the fluorophores. Here, the authors use a spectral FRET anal. on the basis of two excitation wavelengths to obtain a reliable measure of the abs. cAMP concns. with high temporal and spatial resoln. by using an "exchange protein directly activated by cAMP". In this approach, FRET anal. is simplified and does not require addnl. calibration routines. The change in FRET efficiency (E) of the biosensor caused by [cAMP] changes was detd. as ΔE = 15%, whereas E varies between 35% at low and 20% at high [cAMP], allowing quant. measurement of cAMP concn. in the range from 150 nM to 15 μM. The method described is also suitable for other FRET-based biosensors with a 1:1 donor/acceptor stoichiometry. As a proof of principle, the authors measured the spatially resolved cAMP concn. within living cells and detd. the dynamic changes of cAMP levels after stimulation of the Gs-coupled serotonin receptor subtype 7 (5-HT7).
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsVymsbnF&md5=1d9a3939fc5c575fb3aeac55ac1c45fe
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      Prasad, S., Ponimaskin, E., and Zeug, A. (2019) Serotonin receptor oligomerization regulates cAMP-based signaling. J. Cell. Sci. 132, 1,  DOI: 10.1242/jcs.230334
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      Tran, J. A., Pontillo, J., Arellano, M., White, N. S., Fleck, B. A., Marinkovic, D., Tucci, F. C., Lanier, M., Nelson, J., Saunders, J., Foster, A. C., and Chen, C. (2005) Identification of agonists and antagonists of the human melanocortin-4 receptor from piperazinebenzylamines. Bioorg. Med. Chem. Lett. 15, 833– 837,  DOI: 10.1016/j.bmcl.2004.10.096
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      Tran, Joe A.; Pontillo, Joseph; Arellano, Melissa; White, Nicole S.; Fleck, Beth A.; Marinkovic, Dragan; Tucci, Fabio C.; Lanier, Marion; Nelson, Jodie; Saunders, John; Foster, Alan C.; Chen, Chen
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      SAR studies of a series of piperazinebenzylamines resulted in identification of potent agonists and antagonists of the human melanocortin-4 receptor. Thus, the 1,2,3,4-tetrahydroisoquinolin-1-ylacetyl compd. I and its quinolin-3-ylcarbonyl analog possessed Ki values of 6.3 and 4.5 nM, resp. Interestingly, I was a full agonist with an EC50 value of 31 nM, and 12l was a weak partial agonist (IA = 17%) and functioned as an antagonist (IC50 = 300 nM).
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      Lacivita, E., Niso, M., Hansen, H. D., Di Pilato, P., Herth, M. M., Lehel, S., Ettrup, A., Montenegro, L., Perrone, R., Berardi, F. (2014) Design, synthesis, radiolabeling and in vivo evaluation of potential positron emission tomography (PET) radioligands for brain imaging of the 5-HT7 receptor. Bioorg. Med. Chem. 22, 1736– 1750,  DOI: 10.1016/j.bmc.2014.01.016
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      Design, synthesis, radiolabeling and in vivo evaluation of potential positron emission tomography (PET) radioligands for brain imaging of the 5-HT7 receptor
      Lacivita, Enza; Niso, Mauro; Hansen, Hanne D.; Di Pilato, Pantaleo; Herth, Matthias M.; Lehel, Szabolcs; Ettrup, Anders; Montenegro, Lisa; Perrone, Roberto; Berardi, Francesco; Colabufo, Nicola A.; Leopoldo, Marcello; Knudsen, Gitte M.
      Bioorganic & Medicinal Chemistry (2014), 22 (5), 1736-1750CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
      Here we describe the design, synthesis, and pharmacol. evaluation of a set of compds. structurally related to the high affinity serotonin 5-HT7 receptor agonist N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (6, LP-211). Specific structural modifications were performed in order to maintain affinity for the target receptor and to improve the selectivity over 5-HT1A and adrenergic α1 receptors. The synthesized compds. have chem. features that could enable labeling with a positron emitter radioisotope (carbon-11 or fluorine-18) and lipophilicity within the range considered optimal for brain penetration and low non-specific binding. 4-[2-(4-Methoxyphenyl)phenyl]-N-(pyridin-4-ylmethyl)piperazinehexanamide (23a) and N-pyridin-4-ylmethyl-[3-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]ethoxy]propanamide (26a) were radiolabeled on the methoxy group with carbon-11. Positron emission tomog. (PET) anal. revealed that [11C]-23a and [11C]-26a were P-glycoprotein (P-gp) substrates and rapidly metabolized, resulting in poor brain uptake. These features were not predicted by in vitro tests.
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      Kaczor, A. A., Silva, A. G., Loza, M. I., Kolb, P., Castro, M., and Poso, A. (2016) Structure-based virtual screening for dopamine D2 receptor ligands as potential antipsychotics. ChemMedChem 11, 718– 729,  DOI: 10.1002/cmdc.201500599
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      ChemMedChem (2016), 11 (7), 718-729CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Structure-based virtual screening using a D2 receptor homol. model was performed to identify dopamine D2 receptor ligands as potential antipsychotics. From screening a library of 6.5 million compds., 21 were selected and were subjected to exptl. validation. From these 21 compds. tested, ten D2 ligands were identified (47.6 % success rate, among them D2 receptor antagonists, as expected) that have addnl. affinity for other receptors tested, in particular 5-HT2A receptors. The affinity (Ki values) of the compds. ranged from 58 nm to about 24 μm. Similarity and fragment anal. indicated a significant degree of structural novelty among the identified compds. We found one D2 receptor antagonist that did not have a protonatable nitrogen atom, which is a key structural element of the classical D2 pharmacophore model necessary for interaction with the conserved Asp(3.32) residue. This compd. exhibited greater than 20-fold binding selectivity for the D2 receptor over the D3 receptor. We provide addnl. evidence that the amide hydrogen atom of this compd. forms a hydrogen bond with Asp(3.32), as detd. by tests of its derivs. that cannot maintain this interaction.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XksVKqs70%253D&md5=42499f18abc82e57ab9c7849441061e9
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    • General procedures and spectroscopic data of intermediates 7a,b, 12, 13, 15, 16, 19a–c, 22, 23, 24, 25a,b, 26b, 28, and 32a,b; formula, molecular weight, and monoisotopic mass of the synthesized compounds; elemental analysis of target compounds; off-target affinities of selected target compounds; and 1H NMR spectra of target compounds 8a–c, 9, 14a,b, 20a–c, 26a–c, 33a,b, 29, and 30 (PDF)


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