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The First Structure–Activity Relationship Studies for Designer Receptors Exclusively Activated by Designer Drugs
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† Departments of Structural and Chemical Biology, Oncological Sciences, and Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
‡ National Institute of Mental Health - Psychoactive Drug Screening Program, Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
§ Center for Neuro-Medicine, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, Republic of Korea
*(J.J.) Phone: 212-659-8699. E-mail: [email protected]
*(B.L.R.) Phone: 919-966-7535. E-mail: [email protected]
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ACS Chemical Neuroscience

Cite this: ACS Chem. Neurosci. 2015, 6, 3, 476–484
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https://doi.org/10.1021/cn500325v
Published January 14, 2015

Copyright © 2015 American Chemical Society. This publication is licensed under these Terms of Use.

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Abstract

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Over the past decade, two independent technologies have emerged and been widely adopted by the neuroscience community for remotely controlling neuronal activity: optogenetics which utilize engineered channelrhodopsin and other opsins, and chemogenetics which utilize engineered G protein-coupled receptors (Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)) and other orthologous ligand–receptor pairs. Using directed molecular evolution, two types of DREADDs derived from human muscarinic acetylcholine receptors have been developed: hM3Dq which activates neuronal firing, and hM4Di which inhibits neuronal firing. Importantly, these DREADDs were not activated by the native ligand acetylcholine (ACh), but selectively activated by clozapine N-oxide (CNO), a pharmacologically inert ligand. CNO has been used extensively in rodent models to activate DREADDs, and although CNO is not subject to significant metabolic transformation in mice, a small fraction of CNO is apparently metabolized to clozapine in humans and guinea pigs, lessening the translational potential of DREADDs. To effectively translate the DREADD technology, the next generation of DREADD agonists are needed and a thorough understanding of structure–activity relationships (SARs) of DREADDs is required for developing such ligands. We therefore conducted the first SAR studies of hM3Dq. We explored multiple regions of the scaffold represented by CNO, identified interesting SAR trends, and discovered several compounds that are very potent hM3Dq agonists but do not activate the native human M3 receptor (hM3). We also discovered that the approved drug perlapine is a novel hM3Dq agonist with >10 000-fold selectivity for hM3Dq over hM3.

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To elucidate how neuronal ensembles interactively encode higher brain processes, new and improved methods for both recording and manipulating neuronal activity will be required. (1, 2) The ability to selectively modulate the activity of defined neuronal populations and to elucidate the behavioral consequences of this selective neuronal modulation affords powerful approaches for studying mammalian brain function in health and disease. Historically, important methods include Wilder Penfield’s pioneering studies of focal electrical stimulation of the human cortex. (3) The development of the optogenetics technology pioneered by Diesseroth and colleagues to visualize and activate neuronal activity with exquisite temporal resolution using engineered channelrhodopsin (4, 5) and other opsins (6) has provided an expanding toolbox for decoding the neuronal correlates of brain function. (4, 6-10) More recently, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) have been developed as a powerful chemogenetics technology for remotely controlling neuronal activity (11, 12) and have been widely adopted by the neuroscience and greater biological communities. (13-17)
DREADDs, first revealed in 2005, (5) were developed using directed molecular evolution of human muscarinic acetylcholine receptors. (11, 12) After multiple rounds of random mutagenesis, DREADDs derived from the human muscarinic acetylcholine M3 receptors (hM3Dq) to be insensitive to the endogenous ligand acetylcholine (ACh) but potently and selectively activated by the pharmacologically inert clozapine N-oxide (CNO) were discovered. Importantly, CNO lacks appreciable affinity (Ki > 1 μM) for all relevant native CNS (central nervous system) targets. (11, 18) The DREADDs have no detectable constitutive activity in vitro (11) and, thus, provide an attractive orthologous receptor-effector chemogenetic platform for modifying neuronal activity remotely with minimal invasiveness. In addition to hM3Dq, which activates neuronal firing upon the CNO stimulation in part by depolarization and elevation of intracellular calcium levels, (12) hM4Di was developed from human muscarinic acetylcholine M4 receptors for inhibiting neuronal firing via activation of G-protein inwardly rectifying potassium (GIRK) channels. (11) Since the introduction of the DREADD technology, a large number of papers have independently validated the utility of excitatory and inhibitory DREADDs. (12, 19-32) In addition, no effect related to the ectopic expression of hM3Dq or hM4Di has been observed.
In addition to being pharmacologically inert, CNO, the “chemical switch” of this chemogenetic approach, is orally bioavailability and CNS penetrant (19, 33-35) and is not subject to significant metabolic transformation in mice and rats. However, a small fraction of CNO is apparently metabolized to clozapine in humans, nonhuman primates and guinea pigs. (34, 36, 37) Because clozapine modulates the activity of many native CNS receptors, (38) thus interfering with the selective activation of the DREADDs in defined neuronal populations, the “back-metabolism” issue presents a hurdle for translating the DREADD technology forward. To ultimately develop the next generation of DREADD ligands that can selectively activate defined neuronal populations in primates including human, a thorough understanding of structure–activity relationships (SARs) of DREADDs is needed. To date, no SAR studies have been reported for any DREADDs including hM3Dq and hM4Di.
Here, we report the first SAR studies of hM3Dq. We extensively explored multiple regions of the scaffold represented by CNO, which resulted in the discovery of compounds 13 and 21 that are very potent hM3Dq agonists but do not activate the native human M3 receptor (hM3). We describe the design, synthesis, and pharmacological evaluation of new CNO analogues and discuss the interesting SAR trends revealed from the studies. We also report the discovery that perlapine, a hypnotic agent first reported in 1966, (39-41) is a novel, potent, and selective agonist of hM3Dq (>10 000-fold selective for hM3Dq over hM3).

Results and Discussion

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Design and Synthesis

To understand the SAR of CNO analogues as hM3Dq agonists, we explored several regions of the CNO scaffold. In particular, we focused on investigating the R1 and R2 substituents as well as modifications to the piperazine ring (highlighted in red in Figure 1). We also studied whether the chloro group (R3, highlighted in blue in Figure 1) on the tricyclic core is required and whether a different tricyclic core (e.g., the core of the perlapine scaffold, see below) can be tolerated.

Figure 1

Figure 1. SAR studies of the CNO scaffold.

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We first explored the size of the alkyl group (R1) on the N4′ position of the CNO scaffold and synthesized a set of close analogues as outlined in Scheme 1. The commercially available 2-((2-amino-4-chlorophenyl)amino)benzoic acid (1) was refluxed in xylene for 48 h to give the cyclized compound 2, which was then treated with POCl3 and N,N-dimethylaniline in toluene at 95 °C for 2 h to afford the chloride 3. Compound 3 was reacted with various N-alkylpiperazines in toluene at 120 °C for 2 h to yield compounds 4a–4d, which were then converted to their corresponding N-oxides 5a–5d by treating with meta-chloroperoxybenzoic acid (mCPBA) at room temperature in CH2Cl2 for 10 min. The synthetic route to compounds 4a – 4d was described previously. (42, 43)

Scheme 1

Scheme 1. Synthesis of N4′-alkyl Substituted CNO Analoguesa
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Scheme aReagents and conditions: (a) xylene, reflux, 48 h, 95% yield; (b) POCl3, N,N-dimethylaniline, toluene, 95 °C, 2 h, 67% yield; (c) N-alkylpiperazines, toluene, 120 °C, 2 h, 69–80% yield; and (d) mCPBA, CH2Cl2, rt, 10 min, 65–75% yield.

We next synthesized the analogues outlined in Scheme 2 to determine whether the positive charge of CNO is required for activating hM3Dq. For example, compound 6, which contains a quaternary ammonium moiety, has a permanent positive charge, while compounds 7, 9, 12, and 14 do not possess a basic amino group and therefore do not contain a positive charged group. As illustrated in Scheme 2, compound 4a (clozapine) was converted to the quaternary ammonium iodide 6 by stirring overnight with CH3I in acetone at room temperature. Compound 3 was treated with piperazin-2-one at 99 °C overnight in the 1:1 mixture of 1,4-dioxane and ethanol to give compound 7. Similarly, compound 9 was produced by treating compound 3 with commercially available 1,3,8-triazaspiro[4.5]decane-2,4-dione (8) in the 2:1 mixture of 1,4-dioxane and N,N-dimethylformamide (DMF) at 130 °C for 24 h. Hydrolysis of compound 9 using 0.5 N aqueous NaOH solution in 1,2-dimethoxyethane under microwave irradiation afforded compound 10. Likewise, compound 11 was prepared from compound 3 and piperazine in toluene at 120 °C for 2 h. Acetylation of compound 11 by AcCl in CH2Cl2 at 0 °C in the presence of triethylamine (TEA) yielded compound 12, which was subsequently reduced to the deuterated compound 13 using LiAlD4 under reflux conditions, followed by quenching with CD3OD at 0 °C. In addition, compound 11 was reacted with MsCl in CH2Cl2 at 0 °C in the presence of diisopropylethylamine (DIPEA) to give the methylsulfonamide 14.

Scheme 2

Scheme 2. Synthesis of Compounds 6, 7, and 9–14a
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Scheme aReagents and conditions: (a) CH3I, acetone, rt, overnight, 55% yield; (b) 2-oxypiperazine, 1,4-dioxane/ethanol 1:1, 99 °C, overnight, 65% yield; (c) 1,3,8-triazaspiro[4.5]decane-2,4-dione (8), 1,4-dioxane/DMF (2:1), 130 °C, 24 h, 66% yield; (d) 1,2-dimethoxyethane, 0.5 N NaOH, microwave, 150 °C, 10 min, 16% yield; (e) piperazine, toluene, 120 °C, 2 h, 69% yield; (f) AcCl, TEA, CH2Cl2, 0 °C, 1 h, 86% yield; (g) (1) LiAlD4, THF, N2, reflux, 2h, (2) CD3OD, 0 °C, (3) NH4OH, 0 °C, 84% yield; (h) MsCl, DIPEA, CH2Cl2, 0 °C, 1 h, 93% yield.

To determine whether the 8-Cl group on the tricyclic core is required to activate hM3Dq, we prepared compounds 21–23 according to the synthetic route outlined in Scheme 3. (44) The commercially available 2-aminobenzoic acid (15) and 2-nitrophenyl iodide (16) were subjected to Ullmann coupling conditions (45) to afford the aniline 17. Reduction of the nitro moiety of compound 17 yielded compound 18, which was refluxed in xylene to generate the benzodiazepine 19. Treatment of compound 19 with POCl3 provided the chloride 20, which was then displaced with piperazine to afford compound 21. Similarly, compound 22 was prepared by the displacement reaction of the chloride 20 with 1-ethylpiperazine in toluene under reflux conditions. In addition, the oxidation of compound 22 by mCPBA in CH2Cl2 afforded the N-oxide 23.

Scheme 3

Scheme 3. Synthesis of Compounds 22–24a
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Scheme aReagents and conditions: (a) K2CO3, Cu, 3-methylbutan-1-ol, reflux, 4 h; (b) NaS2O4, NH4OH/H2O 3:2, 80 °C, 30 min, 75% yield in two steps; (c) xylene, reflux, Dean–Stark conditions, 48 h, 96% yield; (d) POCl3, N,N-dimethylaniline, toluene, reflux, 3 h, 52% yield; (e) piperazine, toluene, reflux, overnight, 63% yield; (f) 1-ethylpiperazine, toluene, reflux, 2 h, 72% yield; and (g) mCPBA, CH2Cl2, rt, 10 min, 78% yield.

Biological Evaluation

The newly synthesized compounds were evaluated in the hM3Dq and hM3 Ca2+ mobilization fluorometric imaging plate reader (FLIPRTETRA) assays according to the protocols reported previously. (11, 46, 47) Agonist activities of these compounds in the hM3Dq and hM3 functional assays are summarized in Table 1.
Table 1. Agonist Activities of New Compounds in hM3Dq and hM3 FLIPR Assaysa
 hM3DqhM3
compdEC50 (nM)Emax (relative to CNO)EC50 (nM)Emax (relative to acetylcholine)
4a1.19536088
4b7.091>30 000NA
4c1345>30 000NA
4d7150>30 000NA
5a6.0100>30 000NA
5b1950>30 000NA
5c19045>30 000NA
5d74079>30 000NA
60.0691009.592
7>30 000NA>30 000NA
9>30 000NA>30 000NA
10>30 000NA>30 000NA
112.19549086
12>30 000NA>30 000NA
139.686>30 000NA
14>30 000NA>30 000NA
211.7100NA∼20
221.381>30 000NA
2322059>30 000NA
a

EC50 values are the average of at least two duplicate experiments with standard deviation (SD) values that are 3-fold less than the average. NA: not applicable.

For the size of the N-alkyl group in compounds 4a–4d and 5a–5d, we observed a clear trend showing that the longer and/or bulkier the N-alkyl group, the weaker the compounds’ potency for hM3Dq. The replacement of the methyl group in compounds 4a and 5a with the n-propyl group in compounds 4d and 5d resulted in a potency decrease of approximately 70- and 100-fold, respectively. In addition to the loss in potency, the compounds with a longer or bulkier N-alkyl group (e.g., compounds 4b–4d and 5b–5d) in general displayed lower agonist efficacy for hM3Dq and became partial agonists of hM3Dq rather than full agonists as seen for compounds 4a and 5a. Interestingly, compounds 4c and 5c, which contain an i-propyl group, were more potent than compounds 4d and 5d, which contain a n-propyl group, suggesting that the length of the N-alkyl group plays a more significant role than the bulkiness of the N-alkyl group in reducing agonist potency. We were also pleased to find that compounds 4b–4d and 5b–5d did not display any agonist activity (EC50 > 30 000 nM) for the native human M3 receptor (hM3), in contrast to compound 4a (clozapine), which was a hM3 agonist with sub-μM potency. In addition, compounds 4a–4d were in general more potent than their corresponding N-oxides 5a–5d at activating hM3Dq, suggesting that the negative charge on the N-oxides is not only not required for activating hM3Dq, but also reduces agonist potency.
The quaternary ammonium salt 6 was an extremely potent full agonist of hM3Dq with an EC50 value of 69 pM and about 15-fold more potent than compound 4a (clozapine). However, compound 6 was also a potent full agonist of hM3 (EC50 = 9.5 nM, Emax = 92) even though it achieves >100-fold higher potency for hM3Dq over hM3. On the other hand, compounds 7, 12, and 14, which do not contain a basic amino group or a group with permanent positive charge, did not display any agonist activity for hM3Dq. As expected, these compounds did not activate hM3 either. Taken together, these results suggest that either a basic amino group as in compounds 4a and 4b or a group with permanent positive charge as in compounds 5a and 6 is required to retain hM3Dq agonist activity. In addition, compound 9 that contains a hydantoin moiety and compound 10 that contains an amino acid moiety in this region did not activate hM3Dq and hM3. On the other hand, compound 11, which is the des-methyl clozapine, showed similar potency and efficacy for hM3Dq and hM3 as clozapine, suggesting that the N-methyl group is not required for activating hM3Dq. Interestingly, compound 13, which is a deuterated analogue of compound 4b, exhibited similar potency and efficacy (EC50 = 9.6 nM, Emax = 86%) for hM3Dq as compounds 4b and 5a (CNO) (Figure 2). Importantly, compound 13 did not display any agonist activity for hM3. Because compound 13 contains an α,α-dideutero ethyl group, it is likely that the N-dealkylation, the major metabolic pathway that converts clozapine to des-methyl clozapine, (34, 36) will be significantly reduced on the basis of the well-documented primary kinetic isotope effect (48) in similar systems. (49, 50)

Figure 2

Figure 2. Compounds 13 and 21 are potent hM3Dq agonists and do not activate hM3 being similar to compound 5a (CNO). The endogenous ligand acetylcholine (ACh), on the other hand, is a potent hM3 agonist and does not activate hM3Dq.

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We were also pleased to find that the 8-chloro group was not required to maintain high agonist potency and efficacy for hM3Dq. In particular, compound 21 was a potent full agonist (EC50 = 1.7 nM, Emax = 100%) of hM3Dq (Figure 2). In contrast to compound 11, a full hM3 agonist with sub-micromolar potency, compound 21 displayed little agonist activity for hM3 (Emax = ∼20%). In addition, compound 22 was found to be a potent hM3Dq agonist (EC50 = 1.3 nM, Emax = 81%), which was more potent than the corresponding chloro analogue, compound 4b (EC50 = 7.0 nM, Emax = 91%). On the other hand, the N-oxide 23 (EC50 = 220 nM, Emax = 59%) was about 10-fold less potent for hM3Dq than compound 5b, the corresponding chloro analog (EC50 = 19 nM, Emax = 50%). Similar to compound 21, both compounds 22 and 23 did not exhibit any agonist activity for hM3.
We next selected a subset of the above hM3Dq agonists that are inactive against hM3 and assessed their binding affinities to other aminergic GPCRs. Because compound 4a (clozapine) showed high binding affinities to 5HT2A and 5HT2C serotonin, α1A adrenergic, and H1 histamine receptors with Ki values of 5.4, 9.4, 1.6, and 1.1 nM, respectively (Table 2), we tested compounds 4b, 4c, 5b, 5c, 13, and 21 in 5HT2A, 5HT2C, α1A, and H1 radioligand binding assays. The assay results are summarized in Table 2.
Table 2. Binding Affinities of Selected hM3Dq Agonists to Other GPCRsa
 Ki (nM)
compd5HT2A5HT2Cα1AH1
4a5.49.41.61.1
4b2924461.9
4c1617374.6
5b19005100>10 000160
5c520067003206200
1371280675.0
21661702806.0
a

Ki values are the average of at least 2 duplicate experiments with standard deviation (SD) values that are 3-fold less than the average.

Compounds 4b and 4c had reduced binding affinities to 5HT2A, 5HT2C, and α1A (Ki = 16–46 nM) compared with compound 4a (clozapine), but retained high binding affinities to H1 (Ki < 5.0 nM). On the other hand, the N-oxide 5b displayed weak binding affinities for 5HT2A, 5HT2C, and α1A (Ki > 1000 nM) and was about 8-fold selective for hM3Dq over H1, while the N-oxide 5c displayed poor binding affinities to 5HT2A, 5HT2C, and H1 (Ki > 5000 nM) but was only about 2-fold selective for hM3Dq over α1A. Interestingly, compound 13, a deuterated analogue of compound 4b, exhibited reduced binding affinities to all four receptors compared with compound 4b. Compound 13 was selective for hM3Dq over 5HT2A (7-fold), 5HT2C (29-fold), and α1A (7-fold), but was not selective over H1. We were pleased to find that compound 21 displayed much improved selectivity compared with compound 4a (clozapine). In addition to being inactive at hM3, compound 21, a potent full agonist of hM3Dq (EC50 = 1.7 nM), was 40-fold selective over 5HT2A, 100-fold selective over 5HT2C, and 165-fold selective over α1A. Although it was only 3.5-fold selective for hM3Dq over H1, the overall selectivity profile of compound 21 is significantly better than compound 4a (clozapine).
Lastly, to identify an alternative compound that might activate hM3Dq, we conducted a screen of the commercially available Library Of Pharmaceutically Active Compounds (LOPAC; N = 1280 compounds) and Prestwick Chemical Library (N = 1280 compounds) using the hM3Dq FLIPR assay. From this screen, we discovered perlapine as a novel, potent agonist of hM3Dq (Figure 3). Importantly, perlapine was >10 000-fold selective for hM3Dq over hM3. Interestingly, perlapine contains a different tricyclic core in comparison with CNO. The high hM3Dq potency of perlapine suggests that the benzodiazepine tricyclic core of the CNO (compound 5a) scaffold is not required for maintaining high hM3Dq agonist activity.

Figure 3

Figure 3. Perlapine is a potent full agonist of hM3Dq and does not activate hM3. CNO (compound 5a) was used as a positive control in the hM3Dq FLIPR assay, and acetylcholine (ACh) was used as a positive control in the hM3 FLIPR assay.

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Conclusion

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In summary, we conducted the first SAR studies for hM3Dq, a chemogenetic platform for activating neuronal firing, by the design, synthesis, and pharmacological evaluation of new CNO analogues. We explored multiple regions of the CNO scaffold and observed the following interesting SAR trends: (1) a longer or bulkier N-alkyl group as in compounds 4c, 4d, 5c, and 5d reduces both potency and efficacy for hM3Dq; (2) a basic amino group as in compounds 4a and 4b or a permanent positive charge group as in compounds 5a and 6 is required to retain hM3Dq agonist activity; (3) the negative change on the N-oxides such as 5a–5d reduces hM3Dq agonist potency; (4) the 8-chloro group is not required to maintain high agonist potency and efficacy for hM3Dq; and (5) modifications to the benzodiazepine tricyclic core of CNO is tolerated. From these SAR studies, we discovered several compounds such as 13 and 21, which are very potent full agonists of hM3Dq but do not activate the native human M3 receptor (hM3). In addition, the selectivity of compound 21 against a number of aminergic GPCRs is significantly improved compared with clozapine. Furthermore, we discovered perlapine as a novel, potent hM3Dq agonist, which is >10 000-fold selective for hM3Dq over hM3. These SAR studies lay the foundation for developing the next generation of DREADD ligands that can selectively activate defined neuronal populations in primates.

Methods

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Chemistry

General Methods

HPLC spectra of all compounds were acquired from an Agilent 6110 Series system with UV detector set to at 220 nm. Samples were injected (5 μL) onto an Agilent Eclipse Plus 4.6 × 50 mm, 1.8 μM, C18 column at room temperature. A linear gradient from 10% to 100% B (MeOH + 0.1% acetic acid) in 5.0 min was followed by pumping 100% B for another 2 min with A being H2O + 0.1% acetic acid. The flow rate was 1.0 mL/min. Mass spectra (MS) data were acquired in positive ion mode using an Agilent 6110 single quadrupole mass spectrometer with an electrospray ionization (ESI) source. HRMS analysis was conducted on an Agilent Technologies G1969A high-resolution API-TOF mass spectrometer attached to an Agilent Technologies 1200 HPLC system. Samples were ionized by electrospray ionization (ESI) in positive mode. Nuclear magnetic resonance (NMR) spectra were recorded on a Varian Mercury spectrometer with 400 MHz for proton (1H NMR) and 100 MHz for carbon (13C NMR); chemical shifts are reported in ppm (δ). Preparative HPLC was performed on Agilent Prep 1200 series with UV detector set to at 220 nm. Samples were injected onto a Phenomenex Luna 75 × 30 mm, 5 μM, C18 column at room temperature. The flow rate was 30 mL/min. Different linear gradient for different compounds were used with A being H2O + 0.5% TFA and B being MeOH.
Compounds 2, (42, 43)3, (42, 43)4a, (42, 43)4b, (42) and 5a (33, 51) were prepared according to the procedures described previously.
8-Chloro-11-(4-isopropylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine (4c)
A solution of 8,11-dichloro-5H-dibenzo[b,e][1,4]diazepine (3, 0.397 g, 1.44 mmol) and 1-isopropylpiperazine (1 g, 7.799 mmol) in 1,4-dioxane (20 mL) was stirred overnight at 120 °C. After cooling down, the reaction mixture was concentrated and the residue was dissolved with 50 mL of EtOAc. The resulting solution was washed with 30 mL of aqueous NaHCO3. The organic layer was dried over Na2SO4, and the filtrate was concentrated and the residue was purified by flash column chromatography with 5–10% MeOH in CH2Cl2 to give the desired product 4c (0.410 g) in 80% yield: 1H NMR (400 MHz, CDCl3) δ 7.38–7.16 (m, 2H), 7.04 (d, J = 1.5 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H), 6.88–6.72 (m, 2H), 6.58 (d, J = 8.3 Hz, 1H), 4.86 (s, 1H), 3.46 (br, s, 4H), 2.70 (quin, J = 6.5 Hz, 1H), 2.58 (br s, 4H), 1.06 (d, J = 6.5 Hz, 6H). 13C NMR (101 MHz,, CDCl3) δ 162.84, 152.90, 142.13, 140.59, 132.00, 130.55, 129.24, 126.94, 123.69, 123.18, 123.13, 120.25, 120.15, 54.80 (2C), 48.95 (2C), 47.77, 18.80 (2C). HPLC purity 100%, RT 4.099 min. MS (ESI) 355.2 [M + H]+. HRMS (ESI) calcd for C20H24ClN4+ [M + H]+: 355.1689. Found: 355.1693.
8-Chloro-11-(4-propylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine (4d)
Compound 4d (0.380 g, 70% yield) was prepared via the same procedure as preparing compound 4c from 8,11-dichloro-5H-dibenzo[b,e][1,4]diazepine (3, 0.400 g, 1.52 mmol), 1-propylpiperazine HCl salt (0.500 g, 3.04 mmol), and DIPEA (2 mL, 11.48 mmol) in 1,4-dioxane (20 mL). 1H NMR (400 MHz, CDCl3) δ 7.31–7.19 (m, 2H), 7.04 (d, J = 2.3 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H), 6.79 (dd, J = 8.2, 2.0 Hz, 2H), 6.58 (d, J = 8.3 Hz, 1H), 4.86 (s, 1H), 3.45 (br s, 4H), 2.50 (br s, 4H), 2.33 (t, J = 7.6 Hz, 2H), 1.52 (sixtet, J = 7.6 Hz, 2H), 0.90 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 162.93, 152.90, 142.08, 140.59, 132.03, 130.52, 129.25, 126.96, 123.69, 123.21, 123.20, 120.26, 120.16, 60.93 (2C), 53.40 (2C), 47.47, 20.21, 12.18. HPLC purity 100%, RT 4.113 min. MS (ESI) 355.2 [M + H]+. HRMS (ESI) calcd for C20H24ClN4+ [M + H]+: 355.1689. Found: 355.1687.
4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-1-ethylpiperazine N-oxide (5b)
A solution of compound 4b (0.100 g, 0.293 mmol) in CH2Cl2 (5 mL) was treated with mCPBA (0.064 g, 0.371 mmol) at room temperature. After 10 min, the reaction was completed. The resulting mixture was concentrated and purified by flash column chromatography with 5–15% C (2% NH4OH in MeOH) in CH2Cl2 to give the desired N-oxide compound 5b (0.073 g,) in 70% yield: 1H NMR (400 MHz, MeOH-d4) δ 7.39–7.34 (m, 1H), 7.32 (dd, J = 7.8, 1.2 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 2.3 Hz, 1H), 6.87 (dd, J = 8.4, 2.4 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 3.88 (br s, 2H), 3.74 (t, J = 12.1 Hz, 2H), 3.55–3.43 (m, 2H), 3.367 (q, J = 7.2 Hz, 2H), 3.19–3.09 (m, 2H), 1.38 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 162.06, 153.18, 141.54, 140.62, 132.57, 130.29, 129.35, 126.98, 123.90, 123.56, 122.96, 120.45, 120.43, 66.73 (2C), 63.23 (2C), 42.23, 7.69. HPLC purity 100%, RT 4.394 min. MS (ESI) 357.2 [M + H]+. HRMS (ESI) calcd for C19H22ClN4O+ [M + H]+: 357.1482. Found: 357.1481.
4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-1-isopropylpiperazine N-oxide (5c)
Compound 5c (0.068 g, 65% yield) was prepared similarly as 5b from compound 4c (0.100 g, 0.282 mmol) and mCPBA (0.063 g, 0.365 mmol) in CH2Cl2 (5 mL). 1H NMR (400 MHz, MeOH-d4) δ 7.39–7.30 (m, 2H), 7.05 (t, J = 7.5 Hz, 1H), 7.01 (d, J = 7.9 Hz, 1H), 6.97 (d, J = 2.3 Hz, 1H), 6.87 (dd, J = 8.4, 2.4 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 3.90 (br s, 2H), 3.73 (t, J = 11.9 Hz, 1H), 3.57–3.40 (m, 3H), 3.19–3.12 (m, 2H), 1.38 (d, J = 6.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 162.02, 153.15, 141.64, 140.61, 132.51, 130.31, 129.38, 126.97, 123.81, 123.55, 123.01, 120.43, 120.39, 70.99 (2C), 60.41 (2C), 42.27, 16.54 (2C). HPLC purity 100%, RT 4.305 min. MS (ESI) 371.2 [M + H]+. HRMS (ESI) calcd for C20H24ClN4O+ [M + H]+: 371.1639. Found: 371.1642.
4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-1-propylpiperazine N-oxide (5d)
Compound 5d (0.075 g, 72% yield) was prepared using the same procedure as preparing 5b from compound 4d (0.100 g, 0.282 mmol) and mCPBA (0.063 g, 0.365 mmol) in CH2Cl2 (5 mL). 1H NMR (400 MHz, MeOH-d4) δ 7.39–7.34 (m, 1H), 7.32 (dd, J = 7.8, 1.2 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 2.3 Hz, 1H), 6.87 (dd, J = 8.4, 2.4 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 3.86 (br s, 2H), 3.74 (t, J = 11.9 Hz, 3H), 3.57–3.44 (m, 2H), 3.29–3.21 (m, 2H), 3.20–3.10 (m, 2H), 2.00–1.84 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, MeOH-d4) δ 164.31, 155.62, 143.36, 142.96, 133.85, 131.29, 129.72, 127.45, 124.99, 124.29, 124.04, 121.68, 121.53, 73.69 (2C), 64.26 (2C), 43.23, 16.42, 11.37. HPLC purity 100%, RT 4.439 min. MS (ESI) 371.2 [M + H]+. HRMS (ESI) calcd for C20H24ClN4O+ [M + H]+: 371.1639. Found: 371.1640.
4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-1,1-dimethylpiperazin-1-ium iodide (6)
A solution of 4a (0.100 g, 0.306 mmol) in acetone (5 mL) was treated with methyl iodide (21 μL, 0.337 mmol) at room temperature. After overnight, the resulting mixture was concentrated, dissolved in 1 mL of MeOH, and diluted with 10 mL of distilled water. The aqueous solution was washed with EtOAc (2 × 10 mL) and concentrated. The residue was purified by preparative HPLC to give the compound 6 (0.079 g) in 55% yield: 1H NMR (400 MHz, MeOH-d4) δ 7.57 (t, J = 7.7 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.26 (d, J = 2.3 Hz, 1H), 7.27–7.13 (m, 3H), 7.00 (d, J = 8.5 Hz, 1H), 4.03 (br s, 4H), 3.72 (br s, 4H), 3.33 (s, 6H). 13C NMR (101 MHz, MeOH-d4) δ 166.47, 156.55, 145.82, 136.58, 135.26, 132.80, 130.24, 128.46, 126.86, 125.08, 122.75, 122.70, 119.64, 61.86 (2C), 52.46 (2C), 44.44 (2C). HPLC purity 100%, RT 3.893 min. MS (ESI) 341.2 [M − I]+.
4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)piperazin-2-one (7)
A solution of compound 3 (0.200 g, 0.760 mmol) and 2-oxypiperazine (0.152 g, 1.52 mmol) in a 1:1 mixture of 1,4-dioxane and ethanol (15 mL) was stirred overnight at 99 °C. After concentration, the residue was diluted with EtOAc (50 mL) and the solution was washed with 20 mL of aqueous NaHCO3. The organic layer was dried over Na2SO4 and the filtrate was concentrated. The residue was purified by flash column chromatography with 30–50% EtOAc in hexanes to afford the desired product (0.162 g) in 65% yield: 1H NMR (400 MHz, CDCl3) δ 7.30 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.05 (s, 1H), 7.02 (t, J = 7.6 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 6.81 (d, J = 7.9 Hz, 1H), 6.60 (d, J = 8.3 Hz, 1H), 6.03 (s, 1H), 4.90 (s, 1H), 4.10 (s, 2H), 3.67 (br s, 2H), 3.50 (br s, 2H). 13C NMR (101 MHz, CDCl3) δ 168.89, 161.84, 153.15, 141.39, 140.49, 132.63, 130.04, 129.37, 127.19, 124.02, 123.52, 122.99, 120.48, 120.39, 51.47, 44.12, 41.15; HPLC purity 100%, RT 4.681 min. MS (ESI) 327.1 [M + H]+. HRMS (ESI) calcd for C17H16ClN4O+ [M + H]+: 327.1007. Found: 327.1006.
8-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione (9)
A mixture of compound 3 (0.250 g, 0.951 mmol) and commercially available compound 8 (0.200 g, 1.18 mmol) in 20 mL of a mixture of 1,4-dioxane and DMF (2:1) was heated to 130 °C for 24 h. The reaction mixture was cooled down to room temperature and concentrated. The residue was purified by flash column chromatography with 0–10% MeOH in CH2Cl2 to give the desired product 9 (0.250 g) in 66% yield: 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 7.37–7.17 (m, 2H), 7.10–7.03 (m, 2H), 7.01 (t, J = 7.5 Hz, 1H), 6.85–6.76 (m, 2H), 6.62 (d, J = 8.3 Hz, 1H), 5.06 (s, 1H), 3.90 (br s, 2H), 3.20 (br s, 2H), 2.18–2.05 (m, 2H), 1.74 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 176.84, 163.26, 156.74, 152.90, 141.62, 140.70, 132.47, 130.29, 129.42, 126.97, 123.82, 123.59, 123.43, 120.48, 62.15 (2C), 43.28, 33.19 (2C). HPLC purity 100%, RT 4.289 min. MS (ESI) 396.1 [M + H]+. HRMS (ESI) calcd for C20H19ClN5O2+ [M + H]+: 396.1222. Found: 396.1221.
4-Amino-1-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)piperidine-4-carboxylic acid (10)
A solution of compound 9 (0.100 g, 0.253 mmol) in 1,2-dimethoxyethane (5 mL) was treated with 5 mL of 0.5 N NaOH at room temperature. The resulting mixture was heated under microwave for 10 min (max power 100 W, max temperature 150 °C, max pressure 17.0 bar). After cooling down to room temperature, the reaction mixture was quenched with 10% citric acid and filtered. The filtrated was purified with preparative HPLC to afford the desired product (0.015 g) in 16% yield: 1H NMR (400 MHz, MeOH-d4) δ 7.63 (t, J = 7.7 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 19.4 Hz, 1H), 7.25 (t, J = 7.9 Hz, 3H), 7.08 (d, J = 8.6 Hz, 1H), 4.36–3.59 (m, 4H), 2.70–2.40 (m, 2H), 2.40–2.01 (m, 2H). HPLC purity 100%, RT 3.585 min. MS (ESI) 371.2 [M + H]+. HRMS (ESI) calcd for C19H20ClN4O2+ [M + H]+: 371.1269. Found: 371.1264.
Compound 11 was prepared according to the previously published procedures. (42)
1-(4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)piperazin-1-yl)ethanone (12)
To the solution of compound 10 (0.400 g, 1.28 mmol) and TEA (0.27 mL, 2.0 mmol) in CH2Cl2 was added AcCl (0.10 mL, 1.4 mmol) at 0 °C. The resulting mixture was then stirred at 0 °C for 1 h. After removing the solvents, the residue was purified by flash column chromatography with 0–5% MeOH in CH2Cl2 to give the desired product 12 (0.390 g, 1.10 mmol) in 86% yield: 1H NMR (400 MHz, CDCl3) δ 7.30 (td, J = 7.7, 1.5 Hz, 1H), 7.26–7.22 (m, 1H), 7.04 (d, J = 2.4 Hz, 1H), 7.02 (td, J = 7.6, 1.0 Hz, 1H), 6.86–6.77 (m, J = 2.4 Hz, 2H), 6.60 (d, J = 8.3 Hz, 1H), 4.89 (s, 1H), 3.67 (br s, 2H), 3.59–3.46 (m, 4H), 3.34 (br s, 2H), 2.11 (s, J = 11.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 169.41, 162.90, 153.15, 141.57, 140.65, 132.40, 130.20, 129.25, 126.97, 123.75, 123.39, 123.32, 120.42, 120.34, 47.80, 47.26, 46.13, 41.50, 21.62. HPLC purity 100%, RT 4.919 min. MS (ESI) 355.2 [M + H]+. HRMS (ESI) calcd for C19H20ClN4O+ [M + H]+: 355.1320. Found: 355.1315.
8-Chloro-11-[4-(1,1-dideutrioethyl)piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine (13)
To the solution of compound 12 (0.100 g, 0.282 mmol) in 15 mL of anhydrous THF was added LiAlD4 (0.024 g, 0.572 mmol) at room temperature under N2 atmosphere. The reaction mixture was heated under reflux conditions for 2 h. The reaction was quenched with 0.1 mL of CD3OD at 0 °C. The resulting mixture was treated with 0.5 mL of NH4OH at 0 °C and filtered through Celite and the filtrate was concentrated. The residue was purified by flash column chromatography with 0–10% MeOH in CH2Cl2 to give the desired product 13 (0.081 g) in 84% yield: 1H NMR (400 MHz, CDCl3) δ 7.33–7.23 (m, 3H), 7.06 (d, J = 2.4 Hz, 1H), 7.01 (td, J = 7.6, 1.0 Hz, 1H), 6.81 (dd, J = 8.3, 2.4 Hz, 2H), 6.60 (d, J = 8.3 Hz, 1H), 4.88 (s, 1H), 3.49 (br, s, 4H), 2.54 (br, s, 4H), 1.10 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.90, 152.87, 142.03, 140.59, 132.02, 130.46, 129.17, 126.91, 123.60, 123.17, 120.24, 120.16, 52.87 (2C), 51.78 (q, J = 20.0 Hz), 47.44, 11.86 (2C). HPLC purity 100%, RT 4.072 min; MS (ESI) 343.2 [M+1]+. HRMS (ESI) calcd for C19H20D2ClN4+ [M + H]+: 343.1653. Found: 343.1653.
8-Chloro-11-(4-(methylsulfonyl)piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine (14)
To a solution of compound 11 (0.102 g, 0.326 mmol) and DIPEA (87 μL, 0.907 mmol) in 10 mL of CH2Cl2, MsCl (27.8 μL, 0.359 mmol) was added at 0 °C. After 1 h, the reaction was completed. The reaction mixture was diluted with 50 mL of CH2Cl2 and washed with 10 mL of aqueous NaHCO3. The organic layer was dried over Na2SO4, and the filtrate was concentrated and the residue was purified by flash column chromatography with 50% EtOAc in hexanes to give the desired product 14 (0.118 g) in 93% yield: 1H NMR (400 MHz, CDCl3) δ 7.31 (t, J = 7.7 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.08–6.96 (m, 2H), 6.87–6.78 (m, 2H), 6.61 (d, J = 8.3 Hz, 1H), 4.90 (s, 1H), 3.57 (br s, 4H), 3.29 (br s, 4H), 2.79 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 162.44, 154.11, 142.23, 141.48, 132.24, 129.80, 126.69, 125.58, 122.88, 122.64, 122.40, 120.69, 120.40, 46.33, 45.14 (2C), 33.85 (2C). HPLC purity 100%, RT 4.752 min. MS (ESI) 391.1 [M + H]+. HRMS (ESI) calcd for C18H20ClN4O2S+ [M + H]+: 391.0990. Found: 391.0994.
Compounds 17–21 were prepared according to the previously reported procedures. (44)
11-(Piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine (21)
1H NMR (400 MHz, MeOH-d4) δ 7.39–7.24 (m, 1H), 7.06–6.95 (m, 3H), 6.94–6.82 (m, 3H), 3.34 (br s, 1H), 2.96–2.85 (m, 2H). 13C NMR (101 MHz, MeOH-d4) δ 165.39, 156.04, 145.04, 141.55, 133.31, 131.47, 127.85, 125.34, 124.88, 124.66, 123.78, 121.26, 120.71, 46.47. HPLC purity 99%, RT 2.772 min. MS (ESI) 279.2 [M+1]+. HRMS (ESI) calcd for C17H19N4+ [M + H]+: 279.1604. Found: 279.1610.
11-(4-Ethylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine (22)
A solution of compound 20 (0.420 g, 1.84 mmol) and 1-ethylpiperazine (1.5 mL, 11.81 mmol) in toluene (20 mL) was heated under reflux conditions for 2 h. After cooling down to room temperature and concentration, the residue was purified by flash column chromatography with 0–10% MeOH in CH2Cl2 to give the desired product 22 (0.409 g) in 72% yield: 1H NMR (400 MHz, CDCl3) δ 7.30–7.18 (m, 2H), 7.06 (dd, J = 7.8, 1.5 Hz, 1H), 7.00–6.90 (m, 2H), 6.84 (tt, J = 7.3, 3.7 Hz, 1H), 6.80 (dd, J = 7.4, 1.1 Hz, 1H), 6.67 (dd, J = 7.7, 1.4 Hz, 1H), 4.89 (s, 1H), 3.45 (br s, 4H), 2.53 (br s, 4H), 2.46 (q, J = 7.2 Hz, 2H), 1.10 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 162.52, 153.35, 141.97, 140.73, 131.82, 130.54, 127.40, 124.46, 123.86, 123.82, 122.93, 120.16, 119.48, 53.06 (2C), 52.65 (2C), 47.56, 12.18. HPLC purity 100%, RT 3.122 min. MS (ESI) 307.2 [M + H]+. HRMS (ESI) calcd for C19H23N4+ [M + H]+: 307.1917. Found: 307.1918.
4-(5H-Dibenzo[b,e][1,4]diazepin-11-yl)-1-ethylpiperazine N-oxide (23)
A solution of compound 22 (0.095 g, 0.31 mmol) in CH2Cl2 (10 mL) was treated with mCPBA (0.069 g) at room temperature. After 10 min, the reaction mixture was concentrated and the residue was purified with 0–10% C (5% NH4OH in MeOH) in CH2Cl2 to afford the desired product 23 (0.078 g) in 78% yield: 1H NMR (400 MHz, MeOH-d4) δ 7.39–7.29 (m, 2H), 7.07–6.97 (m, 3H), 6.96–6.82 (m, 3H), 3.84 (br s, 2H), 3.79–3.66 (m, 2H), 3.56–3.43 (m, 2H), 3.35 (q, J = 7.0 Hz, 2H), 3.18–3.07 (m, 2H), 1.37 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, MeOH-d4) δ 163.66, 155.93, 144.50, 141.44, 133.64, 131.23, 127.98, 125.69, 125.05, 124.16, 124.13, 121.44, 120.80, 66.90 (2C), 63.79 (2C), 43.32, 7.70. HPLC purity 100%, RT 3.312 min. MS (ESI) 323.2 [M + H]+. HRMS (ESI) calcd for C19H23N4O+ [M + H]+: 323.1866. Found: 323.1863.

Biological Assays

hM3Dq and hM3 FLIPR assays were performed according to the protocols reported previously. (11, 46, 47) Protocols for 5-HT2A, 5-HT2C, α1A, and H1 radioligand binding assays are available at the National Institute of Mental Health–Psychoactive Drug Screening Program Web site (http://pdsp.med.unc.edu/UNC-CH%20Protocol%20Book.pdf).

Author Information

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  • Corresponding Authors
    • Bryan L. Roth - National Institute of Mental Health - Psychoactive Drug Screening Program, Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States;  Email: [email protected]
    • Jian Jin - Departments of Structural and Chemical Biology, Oncological Sciences, and Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States;  Email: [email protected]
  • Authors
    • Xin Chen - Departments of Structural and Chemical Biology, Oncological Sciences, and Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
    • Hyunah Choo - National Institute of Mental Health - Psychoactive Drug Screening Program, Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States;  Center for Neuro-Medicine, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, Republic of Korea
    • Xi-Ping Huang - National Institute of Mental Health - Psychoactive Drug Screening Program, Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
    • Xiaobao Yang - Departments of Structural and Chemical Biology, Oncological Sciences, and Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
    • Orrin Stone - National Institute of Mental Health - Psychoactive Drug Screening Program, Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
  • Author Contributions

    X.C. and H.C. contributed equally to this work. X.C., H.C., X.P.H., X.Y., and O.S. performed the experiments. J.J. and B.L.R. designed the studies. J.J., B.L.R., and X.C. wrote the manuscript.

  • Funding

    This work was supported by the NIH Grant U01MH105892 (to B.L.R. and J.J.) and Korea NRF grant NRF-2013-R1A1A2A10009907 (to H.C.).

  • Notes
    The authors declare no competing financial interest.

Acknowledgment

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We thank Dr. H. Ümit Kaniskan for checking synthetic procedures and NMR spectra of novel compounds.

References

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    Nature (London, United Kingdom) (2009), 458 (7241), 1025-1029CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    In the study of complex mammalian behaviors, technol. limitations have prevented spatiotemporally precise control over intracellular signaling processes. Here we report the development of a versatile family of genetically encoded optical tools ('optoXRs') that leverage common structure-function relationships among G-protein-coupled receptors (GPCRs) to recruit and control, with high spatiotemporal precision, receptor-initiated biochem. signaling pathways. In particular, we have developed and characterized two optoXRs that selectively recruit distinct, targeted signaling pathways in response to light. The two optoXRs exerted opposing effects on spike firing in nucleus accumbens in vivo, and precisely timed optoXR photostimulation in nucleus accumbens by itself sufficed to drive conditioned place preference in freely moving mice. The optoXR approach allows testing of hypotheses regarding the causal impact of biochem. signaling in behaving mammals, in a targetable and temporally precise manner.
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  8. 8
    Berndt, A., Yizhar, O., Gunaydin, L. A., Hegemann, P., and Deisseroth, K. (2009) Bi-stable neural state switches Nat. Neurosci. 12, 229– 234
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    8
    Bi-stable neural state switches
    Berndt, Andre; Yizhar, Ofer; Gunaydin, Lisa A.; Hegemann, Peter; Deisseroth, Karl
    Nature Neuroscience (2009), 12 (2), 229-234CODEN: NANEFN; ISSN:1097-6256. (Nature Publishing Group)
    Here we describe bi-stable channel rhodopsins that convert a brief pulse of light into a stable step in membrane potential. These molecularly engineered probes nevertheless retain millisecond-scale temporal precision. Photocurrents can be precisely initiated and terminated with different colors of light, but operate at vastly longer time scales than conventional channel rhodopsins as a result of modification at the C128 position that extends the lifetime of the open state. Because of their enhanced kinetic stability, these step-function tools are also effectively responsive to light at orders of magnitude lower intensity than wild-type channel rhodopsins. These mols. therefore offer important new capabilities for a broad range of in vivo applications.
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  9. 9
    Li, X., Gutierrez, D. V., Hanson, M. G., Han, J., Mark, M. D., Chiel, H., Hegemann, P., Landmesser, L. T., and Herlitze, S. (2005) Fast noninvasive activation and inhibition of neural and network activity by vertebrate rhodopsin and green algae channelrhodopsin Proc. Natl. Acad. Sci. U. S. A. 102, 17816– 17821
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    9
    Fast noninvasive activation and inhibition of neural and network activity by vertebrate rhodopsin and green algae channelrhodopsin
    Li, Xiang; Gutierrez, Davina V.; Hanson, M. Gartz; Han, Jing; Mark, Melanie D.; Chiel, Hillel; Hegemann, Peter; Landmesser, Lynn T.; Herlitze, Stefan
    Proceedings of the National Academy of Sciences of the United States of America (2005), 102 (49), 17816-17821CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Techniques for fast noninvasive control of neuronal excitability will be of major importance for analyzing and understanding neuronal networks and animal behavior. To develop these tools we demonstrated that two light-activated signaling proteins, vertebrate rat rhodopsin 4 (RO4) and the green algae channelrhodopsin 2 (ChR2), could be used to control neuronal excitability and modulate synaptic transmission. Vertebrate rhodopsin couples to the Gi/o, pertussis toxin-sensitive pathway to allow modulation of G protein-gated inward rectifying potassium channels and voltage-gated Ca2+ channels. Light-mediated activation of RO4 in cultured hippocampal neurons reduces neuronal firing within ms by hyperpolarization of the somato-dendritic membrane, and when activated at presynaptic sites modulates synaptic transmission and paired-pulse facilitation. In contrast, somato-dendritic activation of ChR2 depolarizes neurons sufficiently to induce immediate action potentials, which precisely follow the ChR2 activation up to light stimulation frequencies of 20 Hz. To demonstrate that these constructs are useful for regulating network behavior in intact organisms, embryonic chick spinal cords were electroporated with either construct, allowing the frequency of episodes of spontaneous bursting activity, known to be important for motor circuit formation, to be precisely controlled. Thus light-activated vertebrate RO4 and green algae ChR2 allow the antagonistic control of neuronal function within ms to s in a precise, reversible, and noninvasive manner in cultured neurons and intact vertebrate spinal cords.
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  10. 10
    Zhang, F., Prigge, M., Beyriere, F., Tsunoda, S. P., Mattis, J., Yizhar, O., Hegemann, P., and Deisseroth, K. (2008) Red-shifted optogenetic excitation: a tool for fast neural control derived from Volvox carteri Nat. Neurosci. 11, 631– 633
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    10
    Red-shifted optogenetic excitation: a tool for fast neural control derived from Volvox carteri
    Zhang, Feng; Prigge, Matthias; Beyriere, Florent; Tsunoda, Satoshi P.; Mattis, Joanna; Yizhar, Ofer; Hegemann, Peter; Deisseroth, Karl
    Nature Neuroscience (2008), 11 (6), 631-633CODEN: NANEFN; ISSN:1097-6256. (Nature Publishing Group)
    The introduction of two microbial opsin-based tools, channelrhodopsin-2 (ChR2) and halorhodopsin (NpHR), to neuroscience has generated interest in fast, multimodal, cell type-specific neural circuit control. Here the authors describe a cation-conducting channelrhodopsin (VChR1) from Volvox carteri that can drive spiking at 589 nm, with excitation max. red-shifted ∼70 nm compared with ChR2. These results demonstrate fast photostimulation with yellow light, thereby defining a functionally distinct third category of microbial rhodopsin proteins.
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  11. 11
    Armbruster, B. N., Li, X., Pausch, M. H., Herlitze, S., and Roth, B. L. (2007) Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand Proc. Natl. Acad. Sci. U. S. A. 104, 5163– 5168
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    11
    Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand
    Armbruster Blaine N; Li Xiang; Pausch Mark H; Herlitze Stefan; Roth Bryan L
    Proceedings of the National Academy of Sciences of the United States of America (2007), 104 (12), 5163-8 ISSN:0027-8424.
    We evolved muscarinic receptors in yeast to generate a family of G protein-coupled receptors (GPCRs) that are activated solely by a pharmacologically inert drug-like and bioavailable compound (clozapine-N-oxide). Subsequent screening in human cell lines facilitated the creation of a family of muscarinic acetylcholine GPCRs suitable for in vitro and in situ studies. We subsequently created lines of telomerase-immortalized human pulmonary artery smooth muscle cells stably expressing all five family members and found that each one faithfully recapitulated the signaling phenotype of the parent receptor. We also expressed a G(i)-coupled designer receptor in hippocampal neurons (hM(4)D) and demonstrated its ability to induce membrane hyperpolarization and neuronal silencing. We have thus devised a facile approach for designing families of GPCRs with engineered ligand specificities. Such reverse-engineered GPCRs will prove to be powerful tools for selectively modulating signal-transduction pathways in vitro and in vivo.
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  12. 12
    Alexander, G. M., Rogan, S. C., Abbas, A. I., Armbruster, B. N., Pei, Y., Allen, J. A., Nonneman, R. J., Hartmann, J., Moy, S. S., Nicolelis, M. A., McNamara, J. O., and Roth, B. L. (2009) Remote Control of Neuronal Activity in Transgenic Mice Expressing Evolved G Protein-Coupled Receptors Neuron 63, 27– 39
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    12
    Remote control of neuronal activity in transgenic mice expressing evolved G protein-coupled receptors
    Alexander, Georgia M.; Rogan, Sarah C.; Abbas, Atheir I.; Armbruster, Blaine N.; Pei, Ying; Allen, John A.; Nonneman, Randal J.; Hartmann, John; Moy, Sheryl S.; Nicolelis, Miguel A.; McNamara, James O.; Roth, Bryan L.
    Neuron (2009), 63 (1), 27-39CODEN: NERNET; ISSN:0896-6273. (Cell Press)
    Examg. the behavioral consequences of selective CNS neuronal activation is a powerful tool for elucidating mammalian brain function in health and disease. Newly developed genetic, pharmacol., and optical tools allow activation of neurons with exquisite spatiotemporal resoln.; however, the inaccessibility to light of widely distributed neuronal populations and the invasiveness required for activation by light or infused ligands limit the utility of these methods. To overcome these barriers, we created transgenic mice expressing an evolved G protein-coupled receptor (hM3Dq) selectively activated by the pharmacol. inert, orally bioavailable drug clozapine-N-oxide (CNO). Here, we expressed hM3Dq in forebrain principal neurons. Local field potential and single-neuron recordings revealed that peripheral administration of CNO activated hippocampal neurons selectively in hM3Dq-expressing mice. Behavioral correlates of neuronal activation included increased locomotion, stereotypy, and limbic seizures. These results demonstrate a powerful chem.-genetic tool for remotely controlling the activity of discrete populations of neurons in vivo.
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  13. 13
    Rogan, S. C. and Roth, B. L. (2011) Remote control of neuronal signaling Pharmacol. Rev. 63, 291– 315
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    There is no corresponding record for this reference.
  14. 14
    Farrell, M. S. and Roth, B. L. (2012) Pharmacosynthetics: Reimagining the pharmacogenetic approach Brain Res. 1511, 6– 20
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    There is no corresponding record for this reference.
  15. 15
    Jennings, J. H. and Stuber, G. D. (2014) Tools for Resolving Functional Activity and Connectivity within Intact Neural Circuits Curr. Biol. 24, R41– 50
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    There is no corresponding record for this reference.
  16. 16
    Lee, H. M., Giguere, P. M., and Roth, B. L. (2013) DREADDs: Novel tools for drug discovery and development Drug Discovery Today 19, 469– 473
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    There is no corresponding record for this reference.
  17. 17
    Giguere, P. M., Kroeze, W. K., and Roth, B. L. (2014) Tuning up the right signal: Chemical and genetic approaches to study GPCR functions Curr. Opin. Cell Biol. 27, 51– 55
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    17
    Tuning up the right signal: chemical and genetic approaches to study GPCR functions
    Giguere, Patrick M.; Kroeze, Wesley K.; Roth, Bryan L.
    Current Opinion in Cell Biology (2014), 27 (), 51-55CODEN: COCBE3; ISSN:0955-0674. (Elsevier Ltd.)
    A review. The G protein-coupled receptor (GPCR) family is among the most druggable families in the human proteome. GPCRs are involved in most physiol. processes, and our ability to modulate their activity is a hallmark of modern pharmacol. The means by which the activity of GPCRs can be modulated have been expanded by emerging data and concepts in pharmacol., which has created new strategies for their control. These new approaches will lead to the generation of more potent, selective, and efficient pharmaceutics, while reducing inappropriate actions and adverse effects. Herein, we review and comment on some recent advances in chem. and genetic approaches to the profiling of GPCR function, as well as the validation of orphan GPCRs as potential therapeutic targets using engineered receptors.
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  18. 18
    Armbruster, B. N., Li, X., Pausch, M. H., Herlitze, S., and Roth, B. L. (2007) Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand Proc. Natl. Acad. Sci. U. S. A. 104, 5163– 5168
    Google Scholar
    18
    Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand
    Armbruster Blaine N; Li Xiang; Pausch Mark H; Herlitze Stefan; Roth Bryan L
    Proceedings of the National Academy of Sciences of the United States of America (2007), 104 (12), 5163-8 ISSN:0027-8424.
    We evolved muscarinic receptors in yeast to generate a family of G protein-coupled receptors (GPCRs) that are activated solely by a pharmacologically inert drug-like and bioavailable compound (clozapine-N-oxide). Subsequent screening in human cell lines facilitated the creation of a family of muscarinic acetylcholine GPCRs suitable for in vitro and in situ studies. We subsequently created lines of telomerase-immortalized human pulmonary artery smooth muscle cells stably expressing all five family members and found that each one faithfully recapitulated the signaling phenotype of the parent receptor. We also expressed a G(i)-coupled designer receptor in hippocampal neurons (hM(4)D) and demonstrated its ability to induce membrane hyperpolarization and neuronal silencing. We have thus devised a facile approach for designing families of GPCRs with engineered ligand specificities. Such reverse-engineered GPCRs will prove to be powerful tools for selectively modulating signal-transduction pathways in vitro and in vivo.
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  19. 19
    Ray, R. S., Corcoran, A. E., Brust, R. D., Kim, J. C., Richerson, G. B., Nattie, E., and Dymecki, S. M. (2011) Impaired Respiratory and Body Temperature Control Upon Acute Serotonergic Neuron Inhibition Science 333, 637– 642
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    19
    Impaired Respiratory and Body Temperature Control Upon Acute Serotonergic Neuron Inhibition
    Ray, Russell S.; Corcoran, Andrea E.; Brust, Rachael D.; Kim, Jun Chul; Richerson, George B.; Nattie, Eugene; Dymecki, Susan M.
    Science (Washington, DC, United States) (2011), 333 (6042), 637-642CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    Physiol. homeostasis is essential for organism survival. Highly responsive neuronal networks are involved, but their constituent neurons are just beginning to be resolved. To query brain serotonergic neurons in homeostasis, the authors used a neuronal silencing tool, mouse RC::FPDi (based on the synthetic G protein-coupled receptor Di), designed for cell type-specific, ligand-inducible, and reversible suppression of action potential firing. In mice harboring Di-expressing serotonergic neurons, administration of the ligand clozapine-N-oxide (CNO) by systemic injection attenuated the chemoreflex that normally increases respiration in response to tissue carbon dioxide (CO2) elevation and acidosis. At the cellular level, CNO suppressed firing rate increases evoked by CO2 acidosis. Body thermoregulation at room temp. was also disrupted after CNO triggering of Di; core temps. plummeted, then recovered. This work establishes that serotonergic neurons regulate life-sustaining respiratory and thermoregulatory networks, and demonstrates a noninvasive tool for mapping neuron function.
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  20. 20
    Garner, A. R., Rowland, D. C., Hwang, S. Y., Baumgaertel, K., Roth, B. L., Kentros, C., and Mayford, M. (2012) Generation of a synthetic memory trace Science 335, 1513– 1516
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    There is no corresponding record for this reference.
  21. 21
    Atasoy, D., Betley, J. N., Su, H. H., and Sternson, S. M. (2012) Deconstruction of a neural circuit for hunger Nature 488, 172– 177
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    Krashes, M. J., Shah, B. P., Madara, J. C., Olson, D. P., Strochlic, D. E., Garfield, A. S., Vong, L., Pei, H., Watabe-Uchida, M., Uchida, N., Liberles, S. D., and Lowell, B. B. (2014) An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger Nature 507, 238– 242
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    There is no corresponding record for this reference.
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    Kuhlman, S. J., Olivas, N. D., Tring, E., Ikrar, T., Xu, X., and Trachtenberg, J. T. (2013) A disinhibitory microcircuit initiates critical-period plasticity in the visual cortex Nature 501, 543– 546
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    There is no corresponding record for this reference.
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    Carter, M. E., Soden, M. E., Zweifel, L. S., and Palmiter, R. D. (2013) Genetic identification of a neural circuit that suppresses appetite Nature 503, 111– 114
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    There is no corresponding record for this reference.
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    Vrontou, S., Wong, A. M., Rau, K. K., Koerber, H. R., and Anderson, D. J. (2013) Genetic identification of C fibres that detect massage-like stroking of hairy skin in vivo Nature 493, 669– 673
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    There is no corresponding record for this reference.
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    Kozorovitskiy, Y., Saunders, A., Johnson, C. A., Lowell, B. B., and Sabatini, B. L. (2012) Recurrent network activity drives striatal synaptogenesis Nature 485, 646– 650
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    There is no corresponding record for this reference.
  27. 27
    Ferguson, S. M., Eskenazi, D., Ishikawa, M., Wanat, M. J., Phillips, P. E., Dong, Y., Roth, B. L., and Neumaier, J. F. (2011) Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization Nat. Neurosci. 14, 22– 24
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    27
    Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization
    Ferguson, Susan M.; Eskenazi, Daniel; Ishikawa, Masago; Wanat, Matthew J.; Phillips, Paul E. M.; Dong, Yan; Roth, Bryan L.; Neumaier, John F.
    Nature Neuroscience (2011), 14 (1), 22-24CODEN: NANEFN; ISSN:1097-6256. (Nature Publishing Group)
    Dorsal striatum is important for the development of drug addiction; however, a precise understanding of the roles of striatopallidal (indirect) and striatonigral (direct) pathway neurons in regulating behaviors remains elusive. Using viral-mediated expression of an engineered G protein-coupled receptor (hM4D), we found that activation of hM4D receptors with clozapine-N-oxide (CNO) potently reduced striatal neuron excitability. When hM4D receptors were selectively expressed in either direct or indirect pathway neurons, CNO did not change acute locomotor responses to amphetamine, but did alter behavioral plasticity assocd. with repeated drug treatment. Specifically, transiently disrupting striatopallidal neuronal activity facilitated behavioral sensitization, whereas decreasing excitability of striatonigral neurons impaired its persistence. These findings suggest that acute drug effects can be parsed from the behavioral adaptations assocd. with repeated drug exposure and highlight the utility of this approach for deconstructing neuronal pathway contributions to behavior.
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  28. 28
    Silva, B. A., Mattucci, C., Krzywkowski, P., Murana, E., Illarionova, A., Grinevich, V., Canteras, N. S., Ragozzino, D., and Gross, C. T. (2013) Independent hypothalamic circuits for social and predator fear Nat. Neurosci. 16, 1731– 1733
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    28
    Independent hypothalamic circuits for social and predator fear
    Silva, Bianca A.; Mattucci, Camilla; Krzywkowski, Piotr; Murana, Emanuele; Illarionova, Anna; Grinevich, Valery; Canteras, Newton S.; Ragozzino, Davide; Gross, Cornelius T.
    Nature Neuroscience (2013), 16 (12), 1731-1733CODEN: NANEFN; ISSN:1097-6256. (Nature Publishing Group)
    The neural circuits mediating fear to naturalistic threats are poorly understood. We found that functionally independent populations of neurons in the ventromedial hypothalamus (VMH), a region that has been implicated in feeding, sex and aggression, are essential for predator and social fear in mice. Our results establish a crit. role for VMH in fear and have implications for selective intervention in pathol. fear in humans.
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  29. 29
    Bock, R., Shin, J. H., Kaplan, A. R., Dobi, A., Markey, E., Kramer, P. F., Gremel, C. M., Christensen, C. H., Adrover, M. F., and Alvarez, V. A. (2013) Strengthening the accumbal indirect pathway promotes resilience to compulsive cocaine use Nat. Neurosci. 16, 632– 638
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    29
    Strengthening the accumbal indirect pathway promotes resilience to compulsive cocaine use
    Bock, Roland; Shin, J. Hoon; Kaplan, Alanna R.; Dobi, Alice; Markey, Eric; Kramer, Paul F.; Gremel, Christina M.; Christensen, Christine H.; Adrover, Martin F.; Alvarez, Veronica A.
    Nature Neuroscience (2013), 16 (5), 632-638CODEN: NANEFN; ISSN:1097-6256. (Nature Publishing Group)
    A hallmark of addiction is the loss of control over drug intake, which is seen in only a fraction of those exposed to stimulant drugs such as cocaine. The cellular mechanisms underlying vulnerability or resistance to compulsive drug use remain unknown. We found that individual variability in the development of highly motivated and perseverative behavior toward cocaine is assocd. with synaptic plasticity in medium spiny neurons expressing dopamine D2 receptors (D2-MSNs) in the nucleus accumbens (NAc) of mice. Potentiation of glutamatergic inputs onto indirect pathway D2-MSNs was assocd. with resilience toward compulsive cocaine seeking. Inhibition of D2-MSNs using a chemicogenetic approach enhanced the motivation to obtain cocaine, whereas optogenetic activation of D2-MSNs suppressed cocaine self-administration. These results indicate that recruitment of D2-MSNs in NAc functions to restrain cocaine self-administration and serves as a natural protective mechanism in drug-exposed individuals.
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  30. 30
    Parnaudeau, S., O’Neill, P. K., Bolkan, S. S., Ward, R. D., Abbas, A. I., Roth, B. L., Balsam, P. D., Gordon, J. A., and Kellendonk, C. (2013) Inhibition of mediodorsal thalamus disrupts thalamofrontal connectivity and cognition Neuron 77, 1151– 1162
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    There is no corresponding record for this reference.
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    Brancaccio, M., Maywood, E. S., Chesham, J. E., Loudon, A. S., and Hastings, M. H. (2013) A Gq-Ca2+ axis controls circuit-level encoding of circadian time in the suprachiasmatic nucleus Neuron 78, 714– 728
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    Kong, D., Tong, Q., Ye, C., Koda, S., Fuller, P. M., Krashes, M. J., Vong, L., Ray, R. S., Olson, D. P., and Lowell, B. B. (2012) GABAergic RIP-Cre neurons in the arcuate nucleus selectively regulate energy expenditure Cell 151, 645– 657
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    There is no corresponding record for this reference.
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    Bender, D., Holschbach, M., and Stocklin, G. (1994) Synthesis of n.c.a. carbon-11 labelled clozapine and its major metabolite clozapine-N-oxide and comparison of their biodistribution in mice Nucl. Med. Biol. 21, 921– 925
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    33
    Synthesis of n.c.a. carbon-11 labeled clozapine and its major metabolite clozapine-N-oxide and comparison of their biodistribution in mice
    Bender, D.; Holscbach, M.; Stoecklin, G.
    Nuclear Medicine and Biology (1994), 21 (7), 921-5CODEN: NMBIEO; ISSN:0883-2897.
    N.c.a. [11C]clozapine, [8-chloro-11-(4-[methyl-11C]-methyl-1-piperazinyl)-5H-dibenzo[b,e]-1,4-diazepine], 1, an atypical neuroleptic was synthesized by N-methylation of the desmethyl compd. norclozapine, 3, using [11C]methyl iodide or [11C]methyl triflate for comparison. Subsequent oxidn. of 1 with m-chloroperoxybenzoic acid yielded clozapine-N-oxide, 2, the major metabolite of 1. Purifn. of both radiolabeled products was carried out using a combined semi-preparative HPLC/solid phase extn. procedure. In preparative scale runs overall radiochem. yields for 1 and 2 were 70 and 65%, resp. The radiochem. purities of both compds. exceeded 98% and the specific activities were in the range of 92-130 GBq/μmol (2.5-3.5 Ci/μmol). Biodistribution of 1 and 2 has been studied in NMRI mice. At ten min post injection clozapine shows a 24-fold higher brain uptake than its major metabolite. At 60 min post injection, however, the cerebral uptake of both compds. is almost identical.
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  34. 34
    Chang, W. H., Lin, S. K., Lane, H. Y., Wei, F. C., Hu, W. H., Lam, Y. W. F., and Jann, M. W. (1998) Reversible metabolism of clozapine and clozapine N-oxide in schizophrenic patients Prog. Neuro-Psychopharmacol. 22, 723– 739
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    34
    Reversible metabolism of clozapine and clozapine N-oxide in schizophrenic patients
    Chang, Wen-Ho; Lin, Shih-Ku; Lane, Hsien-Yuan; Wei, Fu-Chuan; Hu, Wei-Herng; Lam, Yw Francis; Jann, Michael W.
    Progress in Neuro-Psychopharmacology & Biological Psychiatry (1998), 22 (5), 723-739CODEN: PNPPD7; ISSN:0278-5846. (Elsevier Science Inc.)
    Our objective was to characterize the interconversion process between clozapine and its metabolite clozapine N-oxide (CNO), eight healthy male schizophrenics were administered a single dose of clozapine or CNO in a randomized crossover manner. Using a general pharmacokinetic model for the interconversion process, the mean total clearances of clozapine and CNO were 28.45 L/h and 45.30 L/h, resp. These values were similar to the values obtained by the usual model-independent method of pharmacokinetic anal. When administered clozapine, mean CNO plasma concns. of 17.7 ± 16.4 ng/mL were slightly lower than the other clozapine metabolite - desmethylclozapine (DCLOZ) plasma levels of 24.4 ± 8.6 ng/mL at the 12 h time point. When CNO was administered, plasma concns. at the 12 h time point of clozapine were twice the amt. of CNO (28.1 ± 8.9 ng/mL vs 14.4 ± 8.8 ng/mL). DCLOZ plasma concns. were detected in all patients upon clozapine administration. Upon CNO administration, only one patient had detectable plasma DCLOZ levels. The interconversion process of clozapine and CNO could partially account for the wide interpatient variability reported for clozapine plasma concns. in schizophrenic patients.
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  • Abstract

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    Figure 1

    Figure 1. SAR studies of the CNO scaffold.

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    Scheme 1

    Scheme 1. Synthesis of N4′-alkyl Substituted CNO Analoguesa
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    Scheme aReagents and conditions: (a) xylene, reflux, 48 h, 95% yield; (b) POCl3, N,N-dimethylaniline, toluene, 95 °C, 2 h, 67% yield; (c) N-alkylpiperazines, toluene, 120 °C, 2 h, 69–80% yield; and (d) mCPBA, CH2Cl2, rt, 10 min, 65–75% yield.

    Scheme 2

    Scheme 2. Synthesis of Compounds 6, 7, and 9–14a
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    Scheme aReagents and conditions: (a) CH3I, acetone, rt, overnight, 55% yield; (b) 2-oxypiperazine, 1,4-dioxane/ethanol 1:1, 99 °C, overnight, 65% yield; (c) 1,3,8-triazaspiro[4.5]decane-2,4-dione (8), 1,4-dioxane/DMF (2:1), 130 °C, 24 h, 66% yield; (d) 1,2-dimethoxyethane, 0.5 N NaOH, microwave, 150 °C, 10 min, 16% yield; (e) piperazine, toluene, 120 °C, 2 h, 69% yield; (f) AcCl, TEA, CH2Cl2, 0 °C, 1 h, 86% yield; (g) (1) LiAlD4, THF, N2, reflux, 2h, (2) CD3OD, 0 °C, (3) NH4OH, 0 °C, 84% yield; (h) MsCl, DIPEA, CH2Cl2, 0 °C, 1 h, 93% yield.

    Scheme 3

    Scheme 3. Synthesis of Compounds 22–24a
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    Scheme aReagents and conditions: (a) K2CO3, Cu, 3-methylbutan-1-ol, reflux, 4 h; (b) NaS2O4, NH4OH/H2O 3:2, 80 °C, 30 min, 75% yield in two steps; (c) xylene, reflux, Dean–Stark conditions, 48 h, 96% yield; (d) POCl3, N,N-dimethylaniline, toluene, reflux, 3 h, 52% yield; (e) piperazine, toluene, reflux, overnight, 63% yield; (f) 1-ethylpiperazine, toluene, reflux, 2 h, 72% yield; and (g) mCPBA, CH2Cl2, rt, 10 min, 78% yield.

    Figure 2

    Figure 2. Compounds 13 and 21 are potent hM3Dq agonists and do not activate hM3 being similar to compound 5a (CNO). The endogenous ligand acetylcholine (ACh), on the other hand, is a potent hM3 agonist and does not activate hM3Dq.

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    Figure 3

    Figure 3. Perlapine is a potent full agonist of hM3Dq and does not activate hM3. CNO (compound 5a) was used as a positive control in the hM3Dq FLIPR assay, and acetylcholine (ACh) was used as a positive control in the hM3 FLIPR assay.

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  • References

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      Penfield, W. and Jasper, H. H. (1954) Epilepsy and the Functional Anatomy of the Human Brain (First ed.), Little Brown, Boston.
      There is no corresponding record for this reference.
    4. 4
      Boyden, E. S., Zhang, F., Bamberg, E., Nagel, G., and Deisseroth, K. (2005) Millisecond-timescale, genetically targeted optical control of neural activity Nat. Neurosci. 8, 1263– 1268
      4
      Millisecond-timescale, genetically targeted optical control of neural activity
      Boyden, Edward S.; Zhang, Feng; Bamberg, Ernst; Nagel, Georg; Deisseroth, Karl
      Nature Neuroscience (2005), 8 (9), 1263-1268CODEN: NANEFN; ISSN:1097-6256. (Nature Publishing Group)
      Temporally precise, noninvasive control of activity in well-defined neuronal populations is a long-sought goal of systems neuroscience. We adapted for this purpose the naturally occurring algal protein Channelrhodopsin-2, a rapidly gated light-sensitive cation channel, by using lentiviral gene delivery in combination with high-speed optical switching to photostimulate mammalian neurons. We demonstrate reliable, millisecond-timescale control of neuronal spiking, as well as control of excitatory and inhibitory synaptic transmission. This technol. allows the use of light to alter neural processing at the level of single spikes and synaptic events, yielding a widely applicable tool for neuroscientists and biomedical engineers.
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    5. 5
      Armbruster, B. N. and Roth, B. L. (2005) Mining the receptorome J. Biol. Chem. 280, 5129– 5132
      There is no corresponding record for this reference.
    6. 6
      Zhang, F., Wang, L. P., Brauner, M., Liewald, J. F., Kay, K., Watzke, N., Wood, P. G., Bamberg, E., Nagel, G., Gottschalk, A., and Deisseroth, K. (2007) Multimodal fast optical interrogation of neural circuitry Nature 446, 633– 639
      6
      Multimodal fast optical interrogation of neural circuitry
      Zhang, Feng; Wang, Li-Ping; Brauner, Martin; Liewald, Jana F.; Kay, Kenneth; Watzke, Natalie; Wood, Phillip G.; Bamberg, Ernst; Nagel, Georg; Gottschalk, Alexander; Deisseroth, Karl
      Nature (London, United Kingdom) (2007), 446 (7136), 633-639CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      The understanding of the cellular implementation of systems-level neural processes like action, thought and emotion has been limited by the availability of tools to interrogate specific classes of neural cells within intact, living brain tissue. Here the authors identify and develop an archaeal light-driven chloride pump (NpHR) from Natronomonas pharaonis for temporally precise optical inhibition of neural activity. NpHR allows either knockout of single action potentials, or sustained blockade of spiking. NpHR is compatible with ChR2, the previous optical excitation technol. the authors have described, in that the two opposing probes operate at similar light powers but with well-sepd. action spectra. NpHR, like ChR2, functions in mammals without exogenous cofactors, and the two probes can be integrated with calcium imaging in mammalian brain tissue for bidirectional optical modulation and readout of neural activity. Likewise, NpHR and ChR2 can be targeted together to Caenorhabditis elegans muscle and cholinergic motor neurons to control locomotion bidirectionally. NpHR and ChR2 form a complete system for multimodal, high-speed, genetically targeted, all-optical interrogation of living neural circuits.
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    7. 7
      Airan, R. D., Thompson, K. R., Fenno, L. E., Bernstein, H., and Deisseroth, K. (2009) Temporally precise in vivo control of intracellular signalling Nature 458, 1025– 1029
      7
      Temporally precise in vivo control of intracellular signalling
      Airan, Raag D.; Thompson, Kimberly R.; Fenno, Lief E.; Bernstein, Hannah; Deisseroth, Karl
      Nature (London, United Kingdom) (2009), 458 (7241), 1025-1029CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      In the study of complex mammalian behaviors, technol. limitations have prevented spatiotemporally precise control over intracellular signaling processes. Here we report the development of a versatile family of genetically encoded optical tools ('optoXRs') that leverage common structure-function relationships among G-protein-coupled receptors (GPCRs) to recruit and control, with high spatiotemporal precision, receptor-initiated biochem. signaling pathways. In particular, we have developed and characterized two optoXRs that selectively recruit distinct, targeted signaling pathways in response to light. The two optoXRs exerted opposing effects on spike firing in nucleus accumbens in vivo, and precisely timed optoXR photostimulation in nucleus accumbens by itself sufficed to drive conditioned place preference in freely moving mice. The optoXR approach allows testing of hypotheses regarding the causal impact of biochem. signaling in behaving mammals, in a targetable and temporally precise manner.
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    8. 8
      Berndt, A., Yizhar, O., Gunaydin, L. A., Hegemann, P., and Deisseroth, K. (2009) Bi-stable neural state switches Nat. Neurosci. 12, 229– 234
      8
      Bi-stable neural state switches
      Berndt, Andre; Yizhar, Ofer; Gunaydin, Lisa A.; Hegemann, Peter; Deisseroth, Karl
      Nature Neuroscience (2009), 12 (2), 229-234CODEN: NANEFN; ISSN:1097-6256. (Nature Publishing Group)
      Here we describe bi-stable channel rhodopsins that convert a brief pulse of light into a stable step in membrane potential. These molecularly engineered probes nevertheless retain millisecond-scale temporal precision. Photocurrents can be precisely initiated and terminated with different colors of light, but operate at vastly longer time scales than conventional channel rhodopsins as a result of modification at the C128 position that extends the lifetime of the open state. Because of their enhanced kinetic stability, these step-function tools are also effectively responsive to light at orders of magnitude lower intensity than wild-type channel rhodopsins. These mols. therefore offer important new capabilities for a broad range of in vivo applications.
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    9. 9
      Li, X., Gutierrez, D. V., Hanson, M. G., Han, J., Mark, M. D., Chiel, H., Hegemann, P., Landmesser, L. T., and Herlitze, S. (2005) Fast noninvasive activation and inhibition of neural and network activity by vertebrate rhodopsin and green algae channelrhodopsin Proc. Natl. Acad. Sci. U. S. A. 102, 17816– 17821
      9
      Fast noninvasive activation and inhibition of neural and network activity by vertebrate rhodopsin and green algae channelrhodopsin
      Li, Xiang; Gutierrez, Davina V.; Hanson, M. Gartz; Han, Jing; Mark, Melanie D.; Chiel, Hillel; Hegemann, Peter; Landmesser, Lynn T.; Herlitze, Stefan
      Proceedings of the National Academy of Sciences of the United States of America (2005), 102 (49), 17816-17821CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Techniques for fast noninvasive control of neuronal excitability will be of major importance for analyzing and understanding neuronal networks and animal behavior. To develop these tools we demonstrated that two light-activated signaling proteins, vertebrate rat rhodopsin 4 (RO4) and the green algae channelrhodopsin 2 (ChR2), could be used to control neuronal excitability and modulate synaptic transmission. Vertebrate rhodopsin couples to the Gi/o, pertussis toxin-sensitive pathway to allow modulation of G protein-gated inward rectifying potassium channels and voltage-gated Ca2+ channels. Light-mediated activation of RO4 in cultured hippocampal neurons reduces neuronal firing within ms by hyperpolarization of the somato-dendritic membrane, and when activated at presynaptic sites modulates synaptic transmission and paired-pulse facilitation. In contrast, somato-dendritic activation of ChR2 depolarizes neurons sufficiently to induce immediate action potentials, which precisely follow the ChR2 activation up to light stimulation frequencies of 20 Hz. To demonstrate that these constructs are useful for regulating network behavior in intact organisms, embryonic chick spinal cords were electroporated with either construct, allowing the frequency of episodes of spontaneous bursting activity, known to be important for motor circuit formation, to be precisely controlled. Thus light-activated vertebrate RO4 and green algae ChR2 allow the antagonistic control of neuronal function within ms to s in a precise, reversible, and noninvasive manner in cultured neurons and intact vertebrate spinal cords.
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    10. 10
      Zhang, F., Prigge, M., Beyriere, F., Tsunoda, S. P., Mattis, J., Yizhar, O., Hegemann, P., and Deisseroth, K. (2008) Red-shifted optogenetic excitation: a tool for fast neural control derived from Volvox carteri Nat. Neurosci. 11, 631– 633
      10
      Red-shifted optogenetic excitation: a tool for fast neural control derived from Volvox carteri
      Zhang, Feng; Prigge, Matthias; Beyriere, Florent; Tsunoda, Satoshi P.; Mattis, Joanna; Yizhar, Ofer; Hegemann, Peter; Deisseroth, Karl
      Nature Neuroscience (2008), 11 (6), 631-633CODEN: NANEFN; ISSN:1097-6256. (Nature Publishing Group)
      The introduction of two microbial opsin-based tools, channelrhodopsin-2 (ChR2) and halorhodopsin (NpHR), to neuroscience has generated interest in fast, multimodal, cell type-specific neural circuit control. Here the authors describe a cation-conducting channelrhodopsin (VChR1) from Volvox carteri that can drive spiking at 589 nm, with excitation max. red-shifted ∼70 nm compared with ChR2. These results demonstrate fast photostimulation with yellow light, thereby defining a functionally distinct third category of microbial rhodopsin proteins.
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    11. 11
      Armbruster, B. N., Li, X., Pausch, M. H., Herlitze, S., and Roth, B. L. (2007) Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand Proc. Natl. Acad. Sci. U. S. A. 104, 5163– 5168
      11
      Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand
      Armbruster Blaine N; Li Xiang; Pausch Mark H; Herlitze Stefan; Roth Bryan L
      Proceedings of the National Academy of Sciences of the United States of America (2007), 104 (12), 5163-8 ISSN:0027-8424.
      We evolved muscarinic receptors in yeast to generate a family of G protein-coupled receptors (GPCRs) that are activated solely by a pharmacologically inert drug-like and bioavailable compound (clozapine-N-oxide). Subsequent screening in human cell lines facilitated the creation of a family of muscarinic acetylcholine GPCRs suitable for in vitro and in situ studies. We subsequently created lines of telomerase-immortalized human pulmonary artery smooth muscle cells stably expressing all five family members and found that each one faithfully recapitulated the signaling phenotype of the parent receptor. We also expressed a G(i)-coupled designer receptor in hippocampal neurons (hM(4)D) and demonstrated its ability to induce membrane hyperpolarization and neuronal silencing. We have thus devised a facile approach for designing families of GPCRs with engineered ligand specificities. Such reverse-engineered GPCRs will prove to be powerful tools for selectively modulating signal-transduction pathways in vitro and in vivo.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2s7nt1egtQ%253D%253D&md5=935cd23bf341eff865375f7d2e253210
    12. 12
      Alexander, G. M., Rogan, S. C., Abbas, A. I., Armbruster, B. N., Pei, Y., Allen, J. A., Nonneman, R. J., Hartmann, J., Moy, S. S., Nicolelis, M. A., McNamara, J. O., and Roth, B. L. (2009) Remote Control of Neuronal Activity in Transgenic Mice Expressing Evolved G Protein-Coupled Receptors Neuron 63, 27– 39
      12
      Remote control of neuronal activity in transgenic mice expressing evolved G protein-coupled receptors
      Alexander, Georgia M.; Rogan, Sarah C.; Abbas, Atheir I.; Armbruster, Blaine N.; Pei, Ying; Allen, John A.; Nonneman, Randal J.; Hartmann, John; Moy, Sheryl S.; Nicolelis, Miguel A.; McNamara, James O.; Roth, Bryan L.
      Neuron (2009), 63 (1), 27-39CODEN: NERNET; ISSN:0896-6273. (Cell Press)
      Examg. the behavioral consequences of selective CNS neuronal activation is a powerful tool for elucidating mammalian brain function in health and disease. Newly developed genetic, pharmacol., and optical tools allow activation of neurons with exquisite spatiotemporal resoln.; however, the inaccessibility to light of widely distributed neuronal populations and the invasiveness required for activation by light or infused ligands limit the utility of these methods. To overcome these barriers, we created transgenic mice expressing an evolved G protein-coupled receptor (hM3Dq) selectively activated by the pharmacol. inert, orally bioavailable drug clozapine-N-oxide (CNO). Here, we expressed hM3Dq in forebrain principal neurons. Local field potential and single-neuron recordings revealed that peripheral administration of CNO activated hippocampal neurons selectively in hM3Dq-expressing mice. Behavioral correlates of neuronal activation included increased locomotion, stereotypy, and limbic seizures. These results demonstrate a powerful chem.-genetic tool for remotely controlling the activity of discrete populations of neurons in vivo.
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    13. 13
      Rogan, S. C. and Roth, B. L. (2011) Remote control of neuronal signaling Pharmacol. Rev. 63, 291– 315
      There is no corresponding record for this reference.
    14. 14
      Farrell, M. S. and Roth, B. L. (2012) Pharmacosynthetics: Reimagining the pharmacogenetic approach Brain Res. 1511, 6– 20
      There is no corresponding record for this reference.
    15. 15
      Jennings, J. H. and Stuber, G. D. (2014) Tools for Resolving Functional Activity and Connectivity within Intact Neural Circuits Curr. Biol. 24, R41– 50
      There is no corresponding record for this reference.
    16. 16
      Lee, H. M., Giguere, P. M., and Roth, B. L. (2013) DREADDs: Novel tools for drug discovery and development Drug Discovery Today 19, 469– 473
      There is no corresponding record for this reference.
    17. 17
      Giguere, P. M., Kroeze, W. K., and Roth, B. L. (2014) Tuning up the right signal: Chemical and genetic approaches to study GPCR functions Curr. Opin. Cell Biol. 27, 51– 55
      17
      Tuning up the right signal: chemical and genetic approaches to study GPCR functions
      Giguere, Patrick M.; Kroeze, Wesley K.; Roth, Bryan L.
      Current Opinion in Cell Biology (2014), 27 (), 51-55CODEN: COCBE3; ISSN:0955-0674. (Elsevier Ltd.)
      A review. The G protein-coupled receptor (GPCR) family is among the most druggable families in the human proteome. GPCRs are involved in most physiol. processes, and our ability to modulate their activity is a hallmark of modern pharmacol. The means by which the activity of GPCRs can be modulated have been expanded by emerging data and concepts in pharmacol., which has created new strategies for their control. These new approaches will lead to the generation of more potent, selective, and efficient pharmaceutics, while reducing inappropriate actions and adverse effects. Herein, we review and comment on some recent advances in chem. and genetic approaches to the profiling of GPCR function, as well as the validation of orphan GPCRs as potential therapeutic targets using engineered receptors.
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    18. 18
      Armbruster, B. N., Li, X., Pausch, M. H., Herlitze, S., and Roth, B. L. (2007) Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand Proc. Natl. Acad. Sci. U. S. A. 104, 5163– 5168
      18
      Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand
      Armbruster Blaine N; Li Xiang; Pausch Mark H; Herlitze Stefan; Roth Bryan L
      Proceedings of the National Academy of Sciences of the United States of America (2007), 104 (12), 5163-8 ISSN:0027-8424.
      We evolved muscarinic receptors in yeast to generate a family of G protein-coupled receptors (GPCRs) that are activated solely by a pharmacologically inert drug-like and bioavailable compound (clozapine-N-oxide). Subsequent screening in human cell lines facilitated the creation of a family of muscarinic acetylcholine GPCRs suitable for in vitro and in situ studies. We subsequently created lines of telomerase-immortalized human pulmonary artery smooth muscle cells stably expressing all five family members and found that each one faithfully recapitulated the signaling phenotype of the parent receptor. We also expressed a G(i)-coupled designer receptor in hippocampal neurons (hM(4)D) and demonstrated its ability to induce membrane hyperpolarization and neuronal silencing. We have thus devised a facile approach for designing families of GPCRs with engineered ligand specificities. Such reverse-engineered GPCRs will prove to be powerful tools for selectively modulating signal-transduction pathways in vitro and in vivo.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2s7nt1egtQ%253D%253D&md5=935cd23bf341eff865375f7d2e253210
    19. 19
      Ray, R. S., Corcoran, A. E., Brust, R. D., Kim, J. C., Richerson, G. B., Nattie, E., and Dymecki, S. M. (2011) Impaired Respiratory and Body Temperature Control Upon Acute Serotonergic Neuron Inhibition Science 333, 637– 642
      19
      Impaired Respiratory and Body Temperature Control Upon Acute Serotonergic Neuron Inhibition
      Ray, Russell S.; Corcoran, Andrea E.; Brust, Rachael D.; Kim, Jun Chul; Richerson, George B.; Nattie, Eugene; Dymecki, Susan M.
      Science (Washington, DC, United States) (2011), 333 (6042), 637-642CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      Physiol. homeostasis is essential for organism survival. Highly responsive neuronal networks are involved, but their constituent neurons are just beginning to be resolved. To query brain serotonergic neurons in homeostasis, the authors used a neuronal silencing tool, mouse RC::FPDi (based on the synthetic G protein-coupled receptor Di), designed for cell type-specific, ligand-inducible, and reversible suppression of action potential firing. In mice harboring Di-expressing serotonergic neurons, administration of the ligand clozapine-N-oxide (CNO) by systemic injection attenuated the chemoreflex that normally increases respiration in response to tissue carbon dioxide (CO2) elevation and acidosis. At the cellular level, CNO suppressed firing rate increases evoked by CO2 acidosis. Body thermoregulation at room temp. was also disrupted after CNO triggering of Di; core temps. plummeted, then recovered. This work establishes that serotonergic neurons regulate life-sustaining respiratory and thermoregulatory networks, and demonstrates a noninvasive tool for mapping neuron function.
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    20. 20
      Garner, A. R., Rowland, D. C., Hwang, S. Y., Baumgaertel, K., Roth, B. L., Kentros, C., and Mayford, M. (2012) Generation of a synthetic memory trace Science 335, 1513– 1516
      There is no corresponding record for this reference.
    21. 21
      Atasoy, D., Betley, J. N., Su, H. H., and Sternson, S. M. (2012) Deconstruction of a neural circuit for hunger Nature 488, 172– 177
      There is no corresponding record for this reference.
    22. 22
      Krashes, M. J., Shah, B. P., Madara, J. C., Olson, D. P., Strochlic, D. E., Garfield, A. S., Vong, L., Pei, H., Watabe-Uchida, M., Uchida, N., Liberles, S. D., and Lowell, B. B. (2014) An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger Nature 507, 238– 242
      There is no corresponding record for this reference.
    23. 23
      Kuhlman, S. J., Olivas, N. D., Tring, E., Ikrar, T., Xu, X., and Trachtenberg, J. T. (2013) A disinhibitory microcircuit initiates critical-period plasticity in the visual cortex Nature 501, 543– 546
      There is no corresponding record for this reference.
    24. 24
      Carter, M. E., Soden, M. E., Zweifel, L. S., and Palmiter, R. D. (2013) Genetic identification of a neural circuit that suppresses appetite Nature 503, 111– 114
      There is no corresponding record for this reference.
    25. 25
      Vrontou, S., Wong, A. M., Rau, K. K., Koerber, H. R., and Anderson, D. J. (2013) Genetic identification of C fibres that detect massage-like stroking of hairy skin in vivo Nature 493, 669– 673
      There is no corresponding record for this reference.
    26. 26
      Kozorovitskiy, Y., Saunders, A., Johnson, C. A., Lowell, B. B., and Sabatini, B. L. (2012) Recurrent network activity drives striatal synaptogenesis Nature 485, 646– 650
      There is no corresponding record for this reference.
    27. 27
      Ferguson, S. M., Eskenazi, D., Ishikawa, M., Wanat, M. J., Phillips, P. E., Dong, Y., Roth, B. L., and Neumaier, J. F. (2011) Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization Nat. Neurosci. 14, 22– 24
      27
      Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization
      Ferguson, Susan M.; Eskenazi, Daniel; Ishikawa, Masago; Wanat, Matthew J.; Phillips, Paul E. M.; Dong, Yan; Roth, Bryan L.; Neumaier, John F.
      Nature Neuroscience (2011), 14 (1), 22-24CODEN: NANEFN; ISSN:1097-6256. (Nature Publishing Group)
      Dorsal striatum is important for the development of drug addiction; however, a precise understanding of the roles of striatopallidal (indirect) and striatonigral (direct) pathway neurons in regulating behaviors remains elusive. Using viral-mediated expression of an engineered G protein-coupled receptor (hM4D), we found that activation of hM4D receptors with clozapine-N-oxide (CNO) potently reduced striatal neuron excitability. When hM4D receptors were selectively expressed in either direct or indirect pathway neurons, CNO did not change acute locomotor responses to amphetamine, but did alter behavioral plasticity assocd. with repeated drug treatment. Specifically, transiently disrupting striatopallidal neuronal activity facilitated behavioral sensitization, whereas decreasing excitability of striatonigral neurons impaired its persistence. These findings suggest that acute drug effects can be parsed from the behavioral adaptations assocd. with repeated drug exposure and highlight the utility of this approach for deconstructing neuronal pathway contributions to behavior.
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    28. 28
      Silva, B. A., Mattucci, C., Krzywkowski, P., Murana, E., Illarionova, A., Grinevich, V., Canteras, N. S., Ragozzino, D., and Gross, C. T. (2013) Independent hypothalamic circuits for social and predator fear Nat. Neurosci. 16, 1731– 1733
      28
      Independent hypothalamic circuits for social and predator fear
      Silva, Bianca A.; Mattucci, Camilla; Krzywkowski, Piotr; Murana, Emanuele; Illarionova, Anna; Grinevich, Valery; Canteras, Newton S.; Ragozzino, Davide; Gross, Cornelius T.
      Nature Neuroscience (2013), 16 (12), 1731-1733CODEN: NANEFN; ISSN:1097-6256. (Nature Publishing Group)
      The neural circuits mediating fear to naturalistic threats are poorly understood. We found that functionally independent populations of neurons in the ventromedial hypothalamus (VMH), a region that has been implicated in feeding, sex and aggression, are essential for predator and social fear in mice. Our results establish a crit. role for VMH in fear and have implications for selective intervention in pathol. fear in humans.
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    29. 29
      Bock, R., Shin, J. H., Kaplan, A. R., Dobi, A., Markey, E., Kramer, P. F., Gremel, C. M., Christensen, C. H., Adrover, M. F., and Alvarez, V. A. (2013) Strengthening the accumbal indirect pathway promotes resilience to compulsive cocaine use Nat. Neurosci. 16, 632– 638
      29
      Strengthening the accumbal indirect pathway promotes resilience to compulsive cocaine use
      Bock, Roland; Shin, J. Hoon; Kaplan, Alanna R.; Dobi, Alice; Markey, Eric; Kramer, Paul F.; Gremel, Christina M.; Christensen, Christine H.; Adrover, Martin F.; Alvarez, Veronica A.
      Nature Neuroscience (2013), 16 (5), 632-638CODEN: NANEFN; ISSN:1097-6256. (Nature Publishing Group)
      A hallmark of addiction is the loss of control over drug intake, which is seen in only a fraction of those exposed to stimulant drugs such as cocaine. The cellular mechanisms underlying vulnerability or resistance to compulsive drug use remain unknown. We found that individual variability in the development of highly motivated and perseverative behavior toward cocaine is assocd. with synaptic plasticity in medium spiny neurons expressing dopamine D2 receptors (D2-MSNs) in the nucleus accumbens (NAc) of mice. Potentiation of glutamatergic inputs onto indirect pathway D2-MSNs was assocd. with resilience toward compulsive cocaine seeking. Inhibition of D2-MSNs using a chemicogenetic approach enhanced the motivation to obtain cocaine, whereas optogenetic activation of D2-MSNs suppressed cocaine self-administration. These results indicate that recruitment of D2-MSNs in NAc functions to restrain cocaine self-administration and serves as a natural protective mechanism in drug-exposed individuals.
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    30. 30
      Parnaudeau, S., O’Neill, P. K., Bolkan, S. S., Ward, R. D., Abbas, A. I., Roth, B. L., Balsam, P. D., Gordon, J. A., and Kellendonk, C. (2013) Inhibition of mediodorsal thalamus disrupts thalamofrontal connectivity and cognition Neuron 77, 1151– 1162
      There is no corresponding record for this reference.
    31. 31
      Brancaccio, M., Maywood, E. S., Chesham, J. E., Loudon, A. S., and Hastings, M. H. (2013) A Gq-Ca2+ axis controls circuit-level encoding of circadian time in the suprachiasmatic nucleus Neuron 78, 714– 728
      There is no corresponding record for this reference.
    32. 32
      Kong, D., Tong, Q., Ye, C., Koda, S., Fuller, P. M., Krashes, M. J., Vong, L., Ray, R. S., Olson, D. P., and Lowell, B. B. (2012) GABAergic RIP-Cre neurons in the arcuate nucleus selectively regulate energy expenditure Cell 151, 645– 657
      There is no corresponding record for this reference.
    33. 33
      Bender, D., Holschbach, M., and Stocklin, G. (1994) Synthesis of n.c.a. carbon-11 labelled clozapine and its major metabolite clozapine-N-oxide and comparison of their biodistribution in mice Nucl. Med. Biol. 21, 921– 925
      33
      Synthesis of n.c.a. carbon-11 labeled clozapine and its major metabolite clozapine-N-oxide and comparison of their biodistribution in mice
      Bender, D.; Holscbach, M.; Stoecklin, G.
      Nuclear Medicine and Biology (1994), 21 (7), 921-5CODEN: NMBIEO; ISSN:0883-2897.
      N.c.a. [11C]clozapine, [8-chloro-11-(4-[methyl-11C]-methyl-1-piperazinyl)-5H-dibenzo[b,e]-1,4-diazepine], 1, an atypical neuroleptic was synthesized by N-methylation of the desmethyl compd. norclozapine, 3, using [11C]methyl iodide or [11C]methyl triflate for comparison. Subsequent oxidn. of 1 with m-chloroperoxybenzoic acid yielded clozapine-N-oxide, 2, the major metabolite of 1. Purifn. of both radiolabeled products was carried out using a combined semi-preparative HPLC/solid phase extn. procedure. In preparative scale runs overall radiochem. yields for 1 and 2 were 70 and 65%, resp. The radiochem. purities of both compds. exceeded 98% and the specific activities were in the range of 92-130 GBq/μmol (2.5-3.5 Ci/μmol). Biodistribution of 1 and 2 has been studied in NMRI mice. At ten min post injection clozapine shows a 24-fold higher brain uptake than its major metabolite. At 60 min post injection, however, the cerebral uptake of both compds. is almost identical.
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    34. 34
      Chang, W. H., Lin, S. K., Lane, H. Y., Wei, F. C., Hu, W. H., Lam, Y. W. F., and Jann, M. W. (1998) Reversible metabolism of clozapine and clozapine N-oxide in schizophrenic patients Prog. Neuro-Psychopharmacol. 22, 723– 739
      34
      Reversible metabolism of clozapine and clozapine N-oxide in schizophrenic patients
      Chang, Wen-Ho; Lin, Shih-Ku; Lane, Hsien-Yuan; Wei, Fu-Chuan; Hu, Wei-Herng; Lam, Yw Francis; Jann, Michael W.
      Progress in Neuro-Psychopharmacology & Biological Psychiatry (1998), 22 (5), 723-739CODEN: PNPPD7; ISSN:0278-5846. (Elsevier Science Inc.)
      Our objective was to characterize the interconversion process between clozapine and its metabolite clozapine N-oxide (CNO), eight healthy male schizophrenics were administered a single dose of clozapine or CNO in a randomized crossover manner. Using a general pharmacokinetic model for the interconversion process, the mean total clearances of clozapine and CNO were 28.45 L/h and 45.30 L/h, resp. These values were similar to the values obtained by the usual model-independent method of pharmacokinetic anal. When administered clozapine, mean CNO plasma concns. of 17.7 ± 16.4 ng/mL were slightly lower than the other clozapine metabolite - desmethylclozapine (DCLOZ) plasma levels of 24.4 ± 8.6 ng/mL at the 12 h time point. When CNO was administered, plasma concns. at the 12 h time point of clozapine were twice the amt. of CNO (28.1 ± 8.9 ng/mL vs 14.4 ± 8.8 ng/mL). DCLOZ plasma concns. were detected in all patients upon clozapine administration. Upon CNO administration, only one patient had detectable plasma DCLOZ levels. The interconversion process of clozapine and CNO could partially account for the wide interpatient variability reported for clozapine plasma concns. in schizophrenic patients.
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    35. 35
      Massey, C. A., Kim, G., Corcoran, A. E., Haynes, R. L., Paterson, D. S., Cummings, K. J., Dymecki, S. M., Richerson, G. B., Nattie, E. E., Kinney, H. C., and Commons, K. G. (2013) Development of brainstem 5HT(1A) receptor-binding sites in serotonin-deficient mice J. Neurochem. 126, 749– 757
      35
      Development of brainstem 5-HT1A receptor-binding sites in serotonin-deficient mice
      Massey, Caitlin A.; Kim, Gloria; Corcoran, Andrea E.; Haynes, Robin L.; Paterson, David S.; Cummings, Kevin J.; Dymecki, Susan M.; Richerson, George B.; Nattie, Eugene E.; Kinney, Hannah C.; Commons, Kathryn G.
      Journal of Neurochemistry (2013), 126 (5&6), 749-757CODEN: JONRA9; ISSN:0022-3042. (Wiley-Blackwell)
      The sudden infant death syndrome is assocd. with a redn. in brainstem 5-hydroxytryptamine (5-HT) and 5-HT1A receptor binding, yet it is unknown if and how these findings are linked. In this study, we used quant. tissue autoradiog. to det. if post-natal development of brainstem 5-HT1A receptors is altered in two mouse models where the development of 5-HT neurons is defective, the Lmx1bf/f/p, and the Pet-1-/- mouse. 5-HT1A receptor agonist-binding sites were examd. in both 5-HT-source nuclei (autoreceptors) and in sites that receive 5-HT innervation (heteroreceptors). In control mice between postnatal day (P) 3 and 10, 5-HT1A receptor binding increased in several brainstem sites; by P25, there were region-specific increases and decreases, refining the overall binding pattern. In the Lmx1bf/f/p and Pet-1-/- mice, 5-HT1A-autoreceptor binding was significantly lower than in control mice at P3, and remained low at P10 and P25. In contrast, 5-HT1A heteroreceptor levels were comparable between control and 5-HT-deficient mice. These data define the postnatal development of 5-HT1A-receptor binding in the mouse brainstem. Furthermore, the data suggest that 5-HT1A-heteroreceptor deficits detected in sudden infant death syndrome are not a direct consequence of a 5-HT neuron dysfunction nor reduced brain 5-HT levels. To elucidate the developmental relationship between serotonin (5-HT) levels and 5-HT1A receptors in the brainstem, we examd. 5-HT1A binding in two 5-HT-deficient mouse models. In nuclei contg. 5-HT neurons, 5-HT1A binding was decreased (autoreceptors), while binding was maintained in projection sites (heteroreceptors). Thus, brainstem 5-HT1A-heteroreceptor-binding sites do not appear developmentally sensitive to reduced brain 5-HT levels.
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    36. 36
      Jann, M. W., Lam, Y. W., and Chang, W. H. (1994) Rapid formation of clozapine in guinea-pigs and man following clozapine-N-oxide administration Arch. Int. Pharmacodyn. Ther. 328, 243– 250
      36
      Rapid formation of clozapine in guinea pigs and man following clozapine-N-oxide administration
      Jann, M. W.; Lam, Y. W. F.; Chang, W. H.
      Archives Internationales de Pharmacodynamie et de Therapie (1994), 328 (2), 243-50CODEN: AIPTAK; ISSN:0003-9780. (Heymans Institute of Pharmacology)
      Clozapine and its metabolite clozapine-N-oxide (0.5 mg/kg) were administered i.p. to guinea-pigs. Significant amts. of clozapine were detected in plasma, liver, frontal cortex and caudate after clozapine-N-oxide administration. Tissue concns. of clozapine in liver, frontal cortex and caudate were greater than plasma concns. Clozapine concns. were almost equiv. in the liver. Clozapine concns. after N-oxide injection were approx. 40-50% lower compared to clozapine concns. after clozapine administration in the frontal cortex and caudate. A single dose of clozapine-N-oxide was given to a schizophrenic patient. Clozapine plasma concns. were detected after N-oxide administration. This study shows that clozapine is formed from its N-oxide metabolite and that a reversible metabolic pathway exists for clozapine and clozapine-N-oxide.
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    37. 37
      Loffler, S., Korber, J., Nubbemeyer, U., and Fehsel, K. (2012) Comment on “Impaired Respiratory and Body Temperature Control Upon Acute Serotonergic Neuron Inhibition” Science 337, 646
      There is no corresponding record for this reference.
    38. 38
      Roth, B. L., Sheffler, D. J., and Kroeze, W. K. (2004) Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia Nat. Rev. Drug Discovery 3, 353– 359
      38
      Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia
      Roth, Bryan L.; Sheffler, Douglas J.; Kroeze, Wesley K.
      Nature Reviews Drug Discovery (2004), 3 (4), 353-359CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
      A review. Most common central nervous system disorders - such as depression, bipolar disorder, and schizophrenia - seem to be polygenic in origin, and the most effective medications have exceedingly complex pharmacologies. Attempts to develop more effective treatments for diseases such as schizophrenia and depression by discovering drugs selective for single mol. targets (i.e., 'magic bullets') have, not surprisingly, been largely unsuccessful. Here the authors propose that designing selectively non-selective drugs (i.e., 'magic shotguns') that interact with several mol. targets will lead to new and more effective medications for a variety of central nervous system disorders.
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    39. 39
      Hunziker, F., Kuenzle, F., and Schmutz, J. (1966) Helv. Chim. Acta 49, 1433– 1439
      There is no corresponding record for this reference.
    40. 40
      Schmutz, J. (1975) Neuroleptic piperazinyl-dibenzo-azepines. Chemistry and structure–activity relationships Arzneimittelforschung 25, 712– 720
      There is no corresponding record for this reference.
    41. 41
      Steiner, G., Franke, A., Hadicke, E., Lenke, D., Teschendorf, H. J., Hofmann, H. P., Kreiskott, H., and Worstmann, W. (1986) Tricyclic epines. Novel (E)- and (Z)-11H-dibenz[b,e]azepines as potential central nervous system agents. Variation of the basic side chain J. Med. Chem. 29, 1877– 1888
      There is no corresponding record for this reference.
    42. 42
      Hunziker, F., Fischer, E., and Schmutz, J. (1967) 11-Amino-5H-Dibenzo[b,e]-1,4-diazepine 0.10. Mitteilung Uber Siebengliedrige Heterocyclen Helv. Chim. Acta 50, 1588– 1599
      There is no corresponding record for this reference.
    43. 43
      Wenthur, C. J. and Lindsley, C. W. (2013) Classics in Chemical Neuroscience: Clozapine ACS Chem. Neurosci. 4, 1018– 1025
      43
      Classics in Chemical Neuroscience: Clozapine
      Wenthur, Cody J.; Lindsley, Craig W.
      ACS Chemical Neuroscience (2013), 4 (7), 1018-1025CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
      A review. Clozapine was the first true breakthrough in schizophrenia treatment since the discovery of chlorpromazine in 1950, effectively treating pos., neg., and some cognitive symptoms, as well as possessing unprecedented efficacy in treatment-resistant patients. Despite over 30 years of intense study, the precise mol. underpinnings that account for clozapine's unique efficacy remain elusive. In this Viewpoint, we will showcase the history and importance of clozapine to neuroscience in general, as well as for the treatment of schizophrenia, and review the synthesis, pharmacol., drug metab., and adverse events of clozapine.
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    44. 44
      Kalhapure, R. S., Patil, B. P., Jadhav, M. N., Kawle, L. A., and Wagh, S. B. (2011) Synthesis of 11-(Piperazin-1-yl)-5H-dibenzo[b,e] [1,4]diazepine on Kilo Scale E-J. Chem. 8, 1747– 1749
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      Synthesis of 11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine on kilo scale
      Kalhapure, Rahul S.; Patil, Bhushan P.; Jadhav, Mahantesh N.; Kawle, Laxmikant A.; Wagh, Sanjay B.
      E-Journal of Chemistry (2011), 8 (4), 1747-1749CODEN: ECJHAO ISSN:. (WWW Publications)
      A synthesis of 11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine on kilo scale without any chromatog. purifn. step was reported. Key steps were Ullmann condensation, catalytic hydrogenation, and catalyzed cyclization.
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    45. 45
      Ullmann, F. and Bielecki, J. (1901) Synthesis in the Biphenyl series. (I. Announcement) Ber. Dtsch. Chem. Ges. 34, 2174– 2185
      There is no corresponding record for this reference.
    46. 46
      Davies, M. A., Compton-Toth, B. A., Hufeisen, S. J., Meltzer, H. Y., and Roth, B. L. (2005) The highly efficacious actions of N-desmethylclozapine at muscarinic receptors are unique and not a common property of either typical or atypical antipsychotic drugs: is M1 agonism a pre-requisite for mimicking clozapine’s actions? Psychopharmacology 178, 451– 460
      There is no corresponding record for this reference.
    47. 47
      Besnard, J., Ruda, G. F., Setola, V., Abecassis, K., Rodriguiz, R. M., Huang, X. P., Norval, S., Sassano, M. F., Shin, A. I., Webster, L. A., Simeons, F. R., Stojanovski, L., Prat, A., Seidah, N. G., Constam, D. B., Bickerton, G. R., Read, K. D., Wetsel, W. C., Gilbert, I. H., Roth, B. L., and Hopkins, A. L. (2012) Automated design of ligands to polypharmacological profiles Nature 492, 215– 220
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      Automated design of ligands to polypharmacological profiles
      Besnard, Jeremy; Ruda, Gian Filippo; Setola, Vincent; Abecassis, Keren; Rodriguiz, Ramona M.; Huang, Xi-Ping; Norval, Suzanne; Sassano, Maria F.; Shin, Antony I.; Webster, Lauren A.; Simeons, Frederick R. C.; Stojanovski, Laste; Prat, Annik; Seidah, Nabil G.; Constam, Daniel B.; Bickerton, G. Richard; Read, Kevin D.; Wetsel, William C.; Gilbert, Ian H.; Roth, Bryan L.; Hopkins, Andrew L.
      Nature (London, United Kingdom) (2012), 492 (7428), 215-220CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      The clin. efficacy and safety of a drug is detd. by its activity profile across many proteins in the proteome. However, designing drugs with a specific multi-target profile is both complex and difficult. Therefore methods to design drugs rationally a priori against profiles of several proteins would have immense value in drug discovery. Here is described a new approach for the automated design of ligands against profiles of multiple drug targets. The method is demonstrated by the evolution of an approved acetylcholinesterase inhibitor drug donepezil (I) into brain-penetrable ligands with either specific polypharmacol. or exquisite selectivity profiles for G-protein-coupled receptors. Overall, 800 ligand-target predictions of prospectively designed ligands were tested exptl., of which 75% were confirmed to be correct. Target engagement in vivo is also demonstrated. The approach can be a useful source of drug leads when multi-target profiles are required to achieve either selectivity over other drug targets or a desired polypharmacol.
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    48. 48
      Wiberg, K. B. (1955) The Deuterium Isotope Effect Chem. Rev. 55, 713– 743
      48
      The deuterium isotope effect
      Wiberg, Kenneth B.
      Chemical Reviews (Washington, DC, United States) (1955), 55 (), 713-43CODEN: CHREAY; ISSN:0009-2665.
      cf. C.A. 49, 13184e. The D isotope effect arises largely from the difference in zero-point energy between a bond to H and the corresponding bond to D. The max. isotope effect is obtained when the bond to H or D is essentially completely cleaved in the activated complex, and the isotope effect decreases with increasing bonding in the activated complex. In general, in any series of related reactions the reaction with the lowest activation energy has the lowest isotope effect. Although the isotope effect is useful in detg. whether a bond to H is cleaved in the rate-detg. step, it must be used with caution; e.g., no isotope effect was noted in the reaction of Grignard reagents with MeOH or H2O, a reaction which probably does involve the cleavage of a bond to H. There is no apparent difference in magnitude for the isotope effect in the removal of H or D as a proton, a hydride ion, or an atom. 241 references.
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    49. 49
      Elison, C., Rapoport, H., Laursen, R., and Elliott, H. W. (1961) Effect of Deuteration of N-CH3 Group on Potency and Enzymatic N-Demethylation of Morphine Science 134, 1078– 1079
      There is no corresponding record for this reference.
    50. 50
      Shao, L., Abolin, C., Hewitt, M. C., Koch, P., and Varney, M. (2006) Derivatives of tramadol for increased duration of effect Bioorg. Med. Chem. Lett. 16, 691– 694
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      Derivatives of tramadol for increased duration of effect
      Shao, Liming; Abolin, Craig; Hewitt, Michael C.; Koch, Patrick; Varney, Mark
      Bioorganic & Medicinal Chemistry Letters (2006), 16 (3), 691-694CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      Tramadol is a centrally acting opioid analgesic structurally related to codeine and morphine. Analogs of tramadol with deuterium-for-hydrogen replacement at metabolically active sites were prepd. and evaluated in vitro and in vivo.
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    51. 51
      Korber, J., Loffler, S., Schollmeyer, D., and Nubbemeyer, U. (2013) Synthesis and Oxidant Properties of Phase 1 Benzepine N-Oxides of Common Antipsychotic Drugs Synthesis 45, 2875– 2887
      There is no corresponding record for this reference.