ACS Publications. Most Trusted. Most Cited. Most Read
Quick View

OR SEARCH CITATIONS

My Activity
Publications
CONTENT TYPES

Figure 1Loading Img
Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Med. Chem. 2014, 57, 10, 4049-4057
RETURN TO ISSUEPREVArticleNEXT

Selectively Promiscuous Opioid Ligands: Discovery of High Affinity/Low Efficacy Opioid Ligands with Substantial Nociceptin Opioid Peptide Receptor Affinity

View Author Information
† Department of Pharmacy and Pharmacology, University of Bath, Bath, BA2 7AY, U.K.
‡ Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, United States
§ School of Chemistry, University of Bristol, Bristol, BS8 1TS, U.K.
∥ College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States
*Phone: 44-(0)1225-383103. E-mail: [email protected]
Cite this: J. Med. Chem. 2014, 57, 10, 4049–4057
Publication Date (Web):April 24, 2014
https://doi.org/10.1021/jm401964y

Copyright © 2022 American Chemical Society. This publication is licensed under these Terms of Use.

Request reuse permissions
  • Open Access

Article Views

3280

Altmetric

-

Citations

18
LEARN ABOUT THESE METRICS
PDF (3 MB)
Get e-Alerts
Supporting Info (1)»
SUBJECTS:

Abstract

High Resolution Image
Download MS PowerPoint Slide

Emerging clinical and preclinical evidence suggests that a compound displaying high affinity for μ, κ, and δ opioid (MOP, KOP, and DOP) receptors and antagonist activity at each, coupled with moderate affinity and efficacy at nociceptin opioid peptide (NOP) receptors will have utility as a relapse prevention agent for multiple types of drug abuse. Members of the orvinol family of opioid ligands have the desired affinity profile but have typically displayed substantial efficacy at MOP and or KOP receptors. In this study it is shown that a phenyl ring analogue (1d) of buprenorphine displays the desired profile in vitro with high, nonselective affinity for the MOP, KOP, and DOP receptors coupled with moderate affinity for NOP receptors. In vivo, 1d lacked any opioid agonist activity and was an antagonist of both the MOP receptor agonist morphine and the KOP receptor agonist ethylketocyclazocine, confirming the desired opioid receptor profile in vivo.

Introduction

ARTICLE SECTIONS
Jump To
The orvinols are a group of ring-C bridged epoxymorphinan compounds that were originally synthesized by Bentley and co-workers (1-3) and developed by Reckitt and Colman. (4) The most studied members of the series include the very potent opiate antagonist diprenorphine (1a) (1) and buprenorphine (1b) (Chart 1), the clinical analgesic and treatment agent for opiate abuse and addiction. (5-8)

Chart 1

High Resolution Image
Download MS PowerPoint Slide
Buprenorphine displays a unique and complex pharmacology derived from the manner in which it binds to opioid receptors. (9-11) At the μ opioid (MOP) receptor it is a partial agonist with high affinity and slow onset and offset, thus having “irreversible” characteristics, manifested in its long duration of action and the mildness of abstinence effects when the drug is withdrawn following chronic administration. At the other opioid receptors, κ (KOP) and δ (DOP) buprenorphine has negligible efficacy and is a potent antagonist of KOP and DOP receptor agonists. In addition to its binding to these classical opioid receptors, buprenorphine also binds as a partial agonist of moderate affinity to the nociceptin opioid peptide (NOP) receptor that, though having a high degree of amino acid sequence homology with the classical opioid receptors, nevertheless has negligible affinity for most opioid ligands. Buprenorphine’s KOP and DOP receptor antagonism and NOP receptor partial agonism appear to contribute to its demonstrated potential as a treatment for cocaine and ethanol abuse and dependence in addition to its approved use in opiate abuse and dependence that is derived from its MOP receptor partial agonism. (8)
Use of buprenorphine to treat cocaine and alcohol abuse would not be allowed in patients without concurrent opiate abuse problems, since buprenorphine treatment supports a significant level of MOP receptor dependence. (7) Thus, one of our medicinal chemistry objectives has been to discover, among structural analogues of buprenorphine, ligands having MOP and KOP receptor antagonist and NOP receptor agonist or partial agonist activity. Such a compound should be more widely useful than buprenorphine in the treatment of cocaine and alcohol abuse and dependence.
Structure–activity relationship studies in orvinols of structures 1 and 2 (Chart 1) based solely on in vivo antinociception data demonstrated that in structure 1 only when R1 and R2 were H or methyl was MOPr antagonist activity shown without accompanying antinociceptive activity. (1, 12) These studies did not rule out the possibility that these MOPr antagonists may have had low efficacy KOPr and DOPr activity below the level required to produce an antinociceptive response in the mouse antiwrithing test. Nevertheless it was clear that when R1 and R2 in structure 1 were alkyl groups larger than methyl, substantial MOPr activity was normally found. Further insight into orvinol SAR has recently been provided with the first publication of affinity and efficacy data for a sizable series of predominantly branched-chain orvinols. (13) Substantial efficacy for MOPr and KOPr was found to be the norm. KOPr agonist efficacy, which would translate in humans as debilitating dysphoric side effects, is dominant. Twenty-five of the 39 compounds tested for KOPr efficacy showed full KOPr agonism (>85% of the response to the full KOPr agonist, U69593), and the others showed a partial KOPr agonist response (30–75% of U69593). The notable exception was buprenorphine, which gave zero KOPr agonist response. Three out of the 40 compounds tested had zero MOPr efficacy, and three had 80% or greater (compared to the full MOPr agonist DAMGO = 100%). The majority, including buprenorphine, demonstrated efficacy between these limits. A CoMFA (comparative molecular field analysis) model developed using this series of ligands suggested that a bulky group immediately adjacent to C20 was key to obtaining low efficacy at KOP receptors when R1 in 1 was larger than methyl.
This led to an investigation of orvinol structures having a large lipophilic moiety directly attached to C20, during which we synthesized a set of phenyl orvinols (1d–f, 2a–c). One of these ligands (1d) was proven to lack any significant MOPr or KOPr efficacy in vitro or in vivo. This led us to synthesize and evaluate a number of analogues. The results of these studies are reported below along with C20-ethyl homologues, as the effect of increasing lipophilicity/bulk through manipulation of the C20-methyl group has also not been explored previously.

Synthesis

ARTICLE SECTIONS
Jump To
All tertiary alcohols were accessed by Grignard addition to the known methyl ketone (8), itself prepared by the recently reported methods of Greedy et al. (Scheme 1). (13) No addition could be achieved with pyridyl Grignard reagents, and so pyridyl lithium addition to the ketone was attempted. This was successful but interestingly gave the opposite diastereomer to that expected (Scheme 1), i.e., opposite to that obtained from standard Grignard addition (confirmed by X-ray crystallography; see Supporting Information). It appears that the reactive aryllithium addition follows the Felkin–Ahn model (14) such that the carbonyl oxygen would be oriented between the large (C6) and medium (C8) neighboring groups, orthogonal to the large (C6) group. Attack of the nucleophile then occurs anti to C6 (Figure 1a). Addition of the less reactive Grignard reagents appears to require initial formation of a six-membered chelate ring (Figure 1b), providing an ordered and activated complex, with nucleophilic addition then occurring from the less hindered (C7-H) face to afford the other epimer. Access to the secondary phenyl alcohols (1e, 1g, 2a, 2b) was via the known aldehydes (11a,b) (13) (Scheme 2). Addition of phenylmagnesium bromide to 11a and 11b gave 12a and 12b, respectively, the opposite diastereoisomer to that obtained on Grignard addition to the methyl ketone (as shown in Scheme 1). Presumably, addition to the more reactive aldehyde does not require formation of the active complex, and so addition follows the Felkin–Ahn model. Subsequent oxidation to 13a and 13b followed by then reduction with lithium aluminum hydride provided the opposite diastereoisomers (14a and 14b). Finally, 3-O-demethylation gave the desired phenolic products 1e and 2a.

Scheme 1

Scheme 1. a

High Resolution Image
Download MS PowerPoint Slide

Scheme aReagents and conditions: (i) RMgBr, THF, rt; (ii) 2-pyridyllithium or 4-pyridyllithium, Et2O, THF, −78 °C → rt; (iii) PrSNa, HMPA, 110 °C or L-selectride, THF, reflux.

Scheme 2

Scheme 2. a

High Resolution Image
Download MS PowerPoint Slide

Scheme aReagents and conditions: (i) PhMgBr, THF, rt; (ii) (COCl)2, DMSO, DMSO, CH2Cl2, −78 °C; (iii) LiAlH4, ether; (iv) PrSNa, HMPA, 110 °C or L-selectride, THF, reflux.

Figure 1

Figure 1. Nucleophilic addition (a) without chelation and (b) with chelation control.

High Resolution Image
Download MS PowerPoint Slide

Results

ARTICLE SECTIONS
Jump To

In Vitro

Opioid receptor binding affinities of the first series of phenyl orvinol analogues (1d–g, 2a–d) were determined by displacement of [3H]DAMGO, [3H]-DPDPE, [3H]U69,593, and [3H]N/OFQ from human opioid receptors transfected into Chinese hamster ovary (CHO) cells. Details of these assays have been described previously. (15)
As expected, in these assays the new compounds all had high affinity for all MOP, DOP, and KOP receptors with no evidence of any selectivity for an individual receptor type (Table 1). Changing R2 from methyl to ethyl (1d to 1f) had no effect on binding affinity, whereas secondary alcohol C20 groups were associated with a slightly lower affinity than tertiary alcohol groups (e.g., 1e versus 1d, 1f), particularly at KOP and DOP receptors. The diasereoisomers 2a and 2b both displayed nonselective binding, though absolute affinities could not be compared because 2b was evaluated in a separate assay. Nevertheless all binding affinities were in the nanomolar range.
Table 1. Binding Affinities (Ki, nM) and stimulation of [35S]GTPγS Binding of Series 1 and 2 to Opioid Receptors
 Ki, nM a,eEC50, nM; % stimb or [Ke, nM]c,e
 MOPKOPDOPNOPMOPKOPDOP
1b1.5 ± 0.802.5 ± 1.26.1 ± 0.4077 ± 1610.2 ± 2.2; 29 ± 1.1NSNS
1c4.0 ± 0.570.56 ± 0.010.86 ± 0.02105 ± 4.050.2 ± 6.6; 40 ± 3.7183 ± 9.4; 73 ± 17>10000
1d0.71 ± 0.170.49 ± 0.081.9 ± 0.33NT[0.47 ± 0.03][0.27 ± 0.03]2.66 ± 0.34; 34 ± 8.0
1e1.3 ± 0.394.4 ± 1.62.6 ± 0.22NT10.4 ± 2.7; 32 ± 5.91.09 ± 0.0; 67 ± 1.44.54 ± 0.58; 90 ± 5.1
1f1.0 ± 0.150.36 ± 0.040.80 ± 0.05396 ± 4118.4 ± 5.7; 18 ± 1.0249 ± 120; 22 ± 4.48.90 ± 1.8; 30 ± 7.5
1g0.82 ± 0.300.88 ± 0.031.3 ± 0.36NT1.55 ± 0.28; 37 ± 1.10.36 ± 0.03; 79 ± 5.00.64 ± 0.17; 113 ± 3.8
2a4.0 ± 0.633.8 ± 0.743.2 ± 0.48NT2.75 ± 1.05; 18 ± 0.92.10 ± 0.49; 70 ± 4.61.76 ± 0.46; 55 ± 0.82
2bd0.80 ± 0.501.5 ± 0.950.40 ± 0.0NTNTNTNT
2c3.2 ± 0.380.95 ± 0.261.2 ± 0.14197 ± 0.2131.8 ± 18.5; 56 ± 1356.6 ± 11; 128 ± 2.410.2 ± 2.4; 123 ± 22
2d4.2 ± 0.600.75 ± 0.111.2 ± 0.16187 ± 27238 ± 19; 84 ± 3.5122 ± 63; 57 ± 5.6314 ± 11; 115 ± 5.2
a

Displacement of [3H]DAMGO, [3H]-DPDPE, [3H]U69,593, and [3H]N/OFQ from human opioid receptors transfected into Chinese hamster ovary (CHO) cells.

b

% maximal stimulation with respect to the standard agonists DAMGO (MOP), U69,593 (KOP), and DPDPE (DOP).

c

Values in brackets are antagonist Ke values versus the standard agonists DAMGO (MOP), U69,593 (KOP), and DPDPE (DOP). Values are the average ± SEM from three separate experiments.

d

Binding to Hartley guinea pig brain membranes, Ki (nM) versus [3H]DAMGO, [3H]DPDPE, [3H]U69,593.

e

NS: no stimulation. NT: not tested.

In the [35S]GTPγS assay for functional opioid activity at MOP, DOP, and KOP receptors using methods reported previously, (15) only 1d was a potent MOP and KOP receptor antagonist (Table 1); it failed to show MOP receptor agonist activity and had very low level KOP receptor efficacy (Table 2). The other phenyl orvinols were MOP receptor partial agonists of efficacy ranging from the low (1f, 2a) to moderately high (2c). They were generally high efficacy KOP receptor partial to full agonists. They showed a similar pattern of agonist efficacy at DOP receptors, at which 1d was also a partial agonist of modest efficacy. It was striking that 1f and 2c which differ structurally only in the 6,14-bridge differed markedly in efficacy for MOP, DOP, and KOP receptor types with the etheno-bridged ligand 2c having markedly higher efficacy.
Table 2. Binding Affinities (Ki, nM) and Maximal Stimulation of [35S]GTPγS Binding of 1d and Analogues to Opioid Receptors
 % stimaKi, nM b
 MOPKOPNOPMOPKOPDOPNOP
1d6.0 ± 119 ± 414 ± 40.17 ± 0.050.044 ± 0.015 43.2 ± 13.4
3a17 ± 490 ± 345 ± 40.19 ± 0.080.16 ± 0.09  
3b33 ± 5102 ± 122 ± 4    
3c50 ± 284 ± 719 ± 5    
3d13 ± 334 ± 314 ± 6    
3e24 ± 750 ± 618 ± 20.28 ± 0.160.10 ± 0.04  
3f14 ± 426 ± 29 ± 5    
3g16 ± 417 ± 312 ± 4    
3h22 ± 277 ± 119 ± 10    
3i18 ± 495 ± 427 ± 2    
4a0 ± 130 ± 67 ± 50.6 ± 0.142.8 ± 0.781.0 ± 0.2275 ± 4.2
4b17 ± 381 ± 144 ± 6    
4c45 ± 379 ± 631 ± 4    
53 ± 279 ± 26 ± 4    
61 ± 339 ± 126 ± 3    
71 ± 3–17 ± 74 ± 30.16 ± 0.040.39 ± 0.090.99 ± 0.434630 ± 380
1b20 ± 60 ± 626 ± 20.13 ± 0.020.089 ± 0.0230.48 ± 0.26212 ± 7
a

Percent maximal stimulation (% stim) at a single high dose (10 μM) with respect to the standard agonists DAMGO (MOP) and U69,593 (KOP) and nociceptin (NOP). Values are an average ± SEM from three separate experiments.

b

Ki (nM) versus [3H]diprenorphine (for MOP and KOP receptors) and [3H]N/OFQ (for NOP receptors). Values are an average ± SEM from three separate experiments.

The effect of replacing the R2 methyl group in buprenorphine (1b) by ethyl was also investigated. The homologue (1c) had comparable affinities at MOP, DOP, and KOP receptors. Affinity for NOP receptors was also measured and compared with that of buprenorphine; again affinities were comparable (Table 1). The etheno analogue (2d) of 1c was also evaluated. Binding affinity for MOP, DOP, and KOP receptors was similar to that of 1c, but NOP receptor affinity was lower. In [35S]GTPγS assays 1c had somewhat higher MOP receptor efficacy than buprenorphine while the etheno analogue (2d) was an almost full MOP receptor agonist though with very modest potency. 1c had high KOP receptor efficacy, whereas buprenorphine is a KOP receptor antagonist; 1c like buprenorphine has no efficacy for DOP receptors. In that respect there was a remarkable difference between 1c and the etheno analogue (2d) which was a full DOP receptor agonist though of low potency.
We followed up on these findings by focusing on close analogues of 1d to identify which had the desired profile of MOP and KOP receptor antagonism. To expedite this process, a primary assay was established whereby compounds were evaluated in the [35S]GTPγS assay for MOP, KOP, and NOP receptor efficacy at a very high concentration (10 μM) to determine peak efficacy at each receptor (Table 2). Nine phenyl substituted analogues of 1d and six analogues with the phenyl group of 1d replaced by heteroaryl rings were evaluated. A limited number of compounds were also evaluated for affinity at MOP, DOP, and KOP receptors by measuring displacement of [3H]diprenorphine binding from C6-rat glioma cells expressing recombinant rat MOP and DOP receptors and CHO cells expressing recombinant human KOP receptors, essentially to confirm the expected high affinity of the series at these receptors. NOP receptor binding affinity was measured by displacement of [3H]N/OFQ from membranes of HEK cells expressing recombinant NOP receptor. Details of these assays have been described previously. (16)
With respect to MOP receptor efficacy, the rank order for the methyl substituted derivatives of 1d was 4′ (3c) > 3′ (3b) > 2′ (3a) > H (1d) (Table 2). All three methyl substituted derivatives were full KOP receptor agonists, whereas NOP receptor efficacy was in the order 2′ > 3′ = 4′ = H. The 4′-isopropyl derivative (3d) had low MOP and NOP receptor efficacy and lower KOP receptor efficacy than the methyl derivative. The 3′- and 4′-chloro derivatives showed all-round low efficacy though slightly higher than for the parent. The 3′- and 4′-fluoro derivatives had low efficacy MOP and NOP receptor agonist activity but high efficacy KOP receptor agonist activity (Table 2).
Screening of the heteroaryl analogues (4, 5, 6, 7) of 1d was undertaken using the same protocols. The 2-thienyl ligand (4a) had zero MOP receptor efficacy in the [35S]GTPγS assay, whereas its 5-methyl (4b) and 5-chloro (4c) substituted derivatives were MOP receptor partial agonists with efficacy respectively similar to and significantly higher than that of buprenorphine (Table 2). 4a had modest KOP receptor efficacy, whereas 4b and 4c were almost full agonists. 4a had low NOP receptor efficacy but had binding affinity for this receptor (Ki = 75 nM) equal to or better than that of buprenorphine (1b) (Ki = 212 nM). The 3-thienyl analogue (5) had MOP and NOP receptor efficacy similar to that of 4a but higher KOP receptor efficacy.
The isomeric 2′- and 4′-pyridyl ligands (6, 7) both had low efficacy for MOP receptor and NOP receptor, but whereas 7 also had no efficacy for KOP receptor, 6 showed distinct KOP receptor activity. In binding assays, 7 showed all-round high affinity for opioid receptors and affinity for NOP receptors equivalent to 1d.

In Vivo

Compound 1d was evaluated in vivo to confirm the lack of MOP and KOP receptor agonism. In the hot-plate test 1d showed no antinociceptive activity and instead was an antagonist of both the MOP receptor agonist morphine and the KOP receptor agonist ethylketocyclazocine (EKC). At 10 mg/kg, 1d caused a parallel shift to the right in the dose–response curve for morphine (Figure 2A), and for EKC there was a complete flattening of the dose–response curve (Figure 2B). The effect of 1d antagonism at both receptors was gone by 24 h.

Figure 2

Figure 2. Antinociceptive effect using the hot-plate assay in mice of (A) morphine and (B) EKC in the absence and presence of 10 mg/kg 1d. 1d was given as a 30 min pretreatment. Morphine and EKC were administered by a cumulative dosing procedure by intraperitoneal (ip) and subcutaneous (sc) injections, respectively, as described. (28)1d was given ip. Vehicle is a 1:1:9 solution of ethanol, emulphor (oil), and sterile water. (29) Data represent the mean ± SEM from five to six mice.

High Resolution Image
Download MS PowerPoint Slide
The hot-plate test uses heat as the nociceptive stimulus and so requires high agonist efficacy in a compound to provide antinociception. (17) Therefore, we checked for agonism in 1d using the lower agonist efficacy requiring acetic acid stretch test. In this test 1d also showed no agonist activity (Figure 3A) up to 32 mg/kg. In contrast buprenorphine was potent and fully efficacious in this assay (Figure 3B), affording an ED50 value (determined by nonlinear regression analysis) of 0.16 mg/kg, similar to the value (0.07 mg/kg) previously reported. (18) These findings confirm that 1d has no, or extremely low, efficacy at MOP or KOP receptors in vivo.

Figure 3

Figure 3. (A) Lack of antinociceptive effect of 1d at 32 mg/kg in the acetic acid stretch assay in mice. (B) Buprenorphine is a full agonist in this assay. The assay was performed as described. (28) Separate groups of mice were used for each dose. Data represent the mean ± SEM from six mice. Vehicle is as in Figure 2. (∗∗∗) p < 0.001; (∗∗∗∗) p < 0.0001.

High Resolution Image
Download MS PowerPoint Slide

Discussion

ARTICLE SECTIONS
Jump To
In this study of analogues of buprenorphine the aim was to identify orvinols with zero or very low efficacy for MOP and KOP receptors together with buprenorphine-like affinity and efficacy for NOP receptors. The criterion of low MOP and KOP receptor efficacy was achieved in several orvinols, but the NOP receptor criterion proved to be very difficult to achieve. The only ligands with NOP receptor efficacy equal or greater than that of buprenorphine (1b) had very much higher KOP receptor efficacy which would be associated with dysphoric side effects in clinical use. From the little data reported to date, finding either significant MOP or KOP receptor efficacy in orvinols that also have affinity and efficacy at NOP receptors is the norm. (19, 20) The most interesting candidate is 1d which satisfies the MOP and KOP receptor efficacy criteria and also has higher binding affinity for NOP receptors than buprenorphine. However, its NOP receptor efficacy is lower than that of buprenorphine. The lack of any activity in the acetic acid induced abdominal stretch assay, which would be expected to indicate even low level MOP or KOP receptor agonist activity and the 52 °C hot-plate antinociceptive assay, confirms, in vivo, the very low efficacy of 1d at MOP and KOP receptors and the promise of 1d as a lead for further investigation.
A surprising finding was the low efficacy of the pyridyl ligands 6 and 7, in particular the latter, at both KOP and MOP receptors. It has previously been shown that the 2° alcohols having opposite relative stereochemistry to buprenorphine, i.e., 15 (Chart 1), are agonists at both receptors, typically full agonists at the KOP receptor. (13) This view was strengthened with the finding that 1g, the phenyl ring analogue of 6 and 7, had high efficacy at KOP receptors as predicted.
SAR at the KOP receptor was striking within this new series. Efficacy ranged from <20% to 100% with clear differences between type of substituent and less consistent differences due to substitution pattern. Of the monosubstituted phenyl analogues the larger substituents such as i-Pr (3d) and chloro (3f, 3g) gave the lowest efficacy analogues while methyl (3a 3c) and fluoro (3h, 3i) gave full efficacy agonists. Molecular modeling of the small-molecule ligands in complex with KOP receptor in the inactive state (PBD code 4DJH) and in the activated conformation was performed as described. (21) The molecular models suggest that the ligands such as 1d interact with the receptor in such a way as to orientate the phenyl ring into a pocket defined by residues from transmembrane helices II (Q115, L135), III (C210 and L135), VII (Y312), and extracellular loops 1 (W124) and 2 (V118, L212) (Figure 4a)

Figure 4

Figure 4. (a) Predicted binding mode for 1d and analogues (magenta) in the KOPr in comparison to the crystal structure ligand JDTic (green). (b) Chloro-substituted analogues of 1d and potential interactions with the KOPr.

High Resolution Image
Download MS PowerPoint Slide
This is the region occupied by the phenolic ring of JDTic in the reported crystal structure. (22) In this antagonist conformation of the receptor, the presence of substituents on the phenyl ring appears to be well tolerated, for example, potentially having interactions with W124 (for 4′-substituents) or Q115 (for 3′-substituents) or L212 and L135 (for 2′-substituents) (Figure 4b). The KOPr binding pocket in the antagonist conformation, defined by the binding of JDTic, is large but narrow and deep and somewhat covered by part of extracellular loop 3. (18) It has been proposed that the active (agonist bound) conformation of the receptor provides an even more restricted binding pocket. (21, 23) It is therefore possible that the larger substituents, Cl and i-Pr in this study, cannot readily fit into the agonist conformation and are therefore predominantly antagonist in character, whereas the smaller substituents (CH3 and F) are easily accommodated in the agonist conformation leading to strong binding to the agonist conformation. However, the low efficacy of the unsubstituted parent (1d) suggests that a small substituent is required for good binding to the agonist conformation.
The C20-ethyl analogues 1c, 1f, 2c, and 2d were all higher efficacy KOP receptor agonists than their C20-methyl homologues. Clearly the ethyl group does not provide the extra bulk around C20 that has been reported to minimize KOP receptor efficacy (13) but is more likely accessing the site below C8 previously identified as a region associated with KOP receptor activation. (24-26)
In vivo evaluation of the lead compound, 1d, confirmed a lack of agonist activity in the hot-plate test and the acetic acid stretch assay which is responsive to low efficacy MOP and KOP receptor agonists. For example, buprenorphine was a fully effective agonist in this assay. The antagonist action of 1d was observed as soon as 30 min after administration but dissipated by 24 h, confirming that 1d is accessing the CNS, in line with its lower predicted log D7.4 than buprenorphine (4.39 versus 4.81) and its predicted level of brain penetration (ACD/I-lab) sufficient for CNS activity.
The aim of generating a ligand with a buprenorphine-like profile but having substantially lower efficacy at MOP receptor has been achieved in part in the current study. 1d is an antagonist at MOP and KOP receptors (though it does have some low efficacy at KOP receptors) and has good affinity, equivalent or better than buprenorphine, for NOP receptors. Efficacy at NOP receptors is, however, lower than displayed by buprenorphine so that the desired profile is not fully realized.

Experimental Section

ARTICLE SECTIONS
Jump To
Reagents and solvents were purchased from Sigma-Aldrich or Alfa Aesar and used as received. Buprenorphine (1b) was supplied by the National Institute on Drug Abuse, Bethesda, MD. 1H and 13C NMR spectra were obtained with a Bruker 400 MHz instrument (1H at 400 MHz, 13C at 100 MHz); δ in ppm, J in Hz with TMS as an internal standard. Instrumentation was as follows: ESIMS, microTOF (Bruker); EIMS, Fisons autosampler; microanalysis, PerkinElmer 240C analyzer. Column chromatography was performed using RediSep prepacked columns with a Teledyne Isco CombiFlash instrument. Ligands were tested as their hydrochloride salts, prepared by adding 5 equiv of HCl (1 N solution in diethyl ether) to a solution of compound in anhydrous methanol. All reactions were carried out under an inert atmosphere of nitrogen unless otherwise indicated. All compounds were >95% pure as determined by microanalysis. A representative synthesis for each series is reported here.

General Procedure A: 3-O-Demethylation with Propanethiolate and HCl Salt Formation

A solution of the appropriate thevinol (0.25 mmol) in anhydrous HMPA (1 mL) under an inert atmosphere was treated with sodium hydride (21 mg, 0.875 mmol) followed by 1-propanethiol (79 μL, 0.875 mmol). After the addition was complete, the reaction mixture was heated to 120 °C and stirred for 3 h. When the mixture was cooled to room temperature, NH4Cl (sat., aq) was added and the mixture extracted with diethyl ether. The organic extracts were washed with water (3×) and brine. The organic phase was dried (MgSO4), filtered, and evaporated to dryness. The residue was purified by column chromatography over silica gel. The HCl salts were prepared by the addition of 2 M HCl in diethyl ether (1.2 equiv) to a solution of the orvinol in diethyl ether. The white precipitate that formed was collected by filtration, washed with ether, and dried under high vacuum.

(1′S,5α,6R,7R,14α)-1′-(4,5-Epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-1′-phenylethan-1′-ol (1d)

N-CPM dihydronorthevinone 8a (220 mg, 0.52 mmol) in anhydrous toluene (5.2 mL) was treated with phenylmagnesium bromide (1.5 mL, 1.04 mmol) at room temperature for 22 h. Purification using column chromatography (30% EtOAc–petroleum ether–0.5% NH3) gave thevinol 9a (R = Ph), (110 mg, 42%). Rf (30% EtOAc–petroleum ether–0.5% NH3) 0.7. δH (CDCl3) 7.50 (2H, d), 7.33 (2H, t), 7.18–7.26 (1H, m), 6.69 (1H, d), 6.52 (1H, d), 5.50 (1H, s), 4.42 (1H, s), 3.87 (3H, s), 3.61 (3H, s), 2.91 (1H, d), 2.86 (1H, d), 2.39–2.44 (1H, m), 2.11–2.55 (5H, m), 1.87–1.99 (1H, m), 1.79–1.86 (2H, m), 1.79 (3H, s), 1.54–1.58 (1H, m), 0.77–1.07 (3H, m), 0.55–0.73 (1H, m), 0.33–0.39 (2H, m), −0.10 to −0.03 (2H, m). δC (CDCl3) 147.46, 146.94, 141.66, 132.76, 128.98, 127.92, 126.79, 126.17, 119.18, 113.97, 97.14, 80.87, 59.54, 57.97, 56.90, 53.00, 48.57, 46.95, 43.52, 36.03, 35.70, 32.65, 30.06, 23.58, 22.72, 17.97, 9.35, 4.18, 3.32. m/z for C32H40NO4, [MH]+ calcd 502.2957. Found 502.2958. 9a (R = Ph) (103 mg, 0.21 mmol) was treated as in procedure A to yield 1d after silica gel chromatography (30% EtOAc–petroleum ether–0.5% NH3) (40.0 mg, 39%). Rf (30% EtOAc–petroleum ether–0.5% NH3) 0.2. δH (CDCl3) 7.50 (2H, d), 7.32 (2H, t), 7.18–7.26 (1H, m). 6.62 (1H, d), 6.45 (1H, d), 5.58 (1H, s), 4.60 (1H, s), 4.42 (1H, s), 3.56 (3H, s), 2.89 (1H, d), 2.84 (1H, d), 2.40–2.42 (1H, m), 2.10–2.19 (5H, m), 1.90–2.08 (1H, m), 1.72–1.84 (3H, m), 1.80 (3H, s), 1.54–1.58 (1H, m), 1.02–1.10 (1H, m), 0.89–0.94 (1H, dd), 0.69–0.76 (1H, m), 0.56–0.65 (1H, m), 0.30–0.40 (2H, m), −0.1 to 0 (2H, m); δC (CDCl3) 147.27, 132.44, 127.93, 126.83, 126.14, 119.56, 116.51, 97.39, 80.92, 59.52, 58.01, 52.91, 48.48, 47.24, 43.53, 36.10, 35.60, 32.60, 29.95, 23.59, 22.80, 17.97, 9.32, 4.15, 3.31. m/z found [MH]+ 488.2778. C31H38NO4 requires 488.2801. Anal. (C31H38ClNO4) C, H, N.

(1′S,5α,6R,7R,14α)-1′-(4,5-Epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethenomorphinan-7-yl)-1′-phenylmethanol (2a)

The alcohol 14b (500 mg, 1.03 mmol) was treated as in procedure A to yield 2a, which was purified by gravity elution chromatography with MeOH–CH2Cl2. (1:20) (370 mg, 76%). Rf (MeOH–CH2Cl2, 1:10) 0.48. NMR δH (CDCl3) 0.38–0.40 (2H, m), 0.40–0.53 (2H, m), 0.64–0.66 (1H, m), 3.01 (1H, d), 3.35 (1H, d), 3.80 (3H, s), 4.35 (1H, d), 4.65 (1H, d), 5.43 (1H, s), 5.56 (1H, d), 6.00 (1H, d), 6.43 (1H, d), 6.55 (1H, d), 7.26–7.32 (5H, m). δC (CDCl3) 3.52, 3.98, 9.18, 23.03, 30.38, 33.00, 42.59, 43.83, 43.92, 47.76, 54.86, 57.04, 59.85, 77.70, 84.53, 97.79, 116.26, 119.83, 124.37, 125.77, 127.70, 128.09, 128.23, 134.32, 137.54, 137.78, 141.71, 146.33. m/z found M+ for C30H33NO4, 471.2404; calculated 471.2410. Mp (HCl salt) 227–231 °C (dec, EtOH). Anal. (C30H34ClNO4·H2O) C, H, N.

(1′R,5α,6R,7R, 14α)-1′-(4,5-Epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethenomorphinan-7-yl)-1′-phenylmethanol (2b)

The alcohol 12b (550 mg, 1.13 mmol) was treated as in procedure A to yield 2b which was purified by gravity elution chromatography with MeOH–CH2Cl2. (1:20) (470 mg, 88%). Rf (MeOH–CH2Cl2, 1:10) 0.48. NMR δH (CDCl3) 0.01–0.08 (2H, m), 0.45–0.49 (2H, m), 0.74–0.76 (1H, m), 1.37 (1H, dd), 3.05 (1H, d), 3.53 (1H, d), 3.69 (3H, s), 4.62 (1H, d), 5.20 (1H, s), 5.49 (1H, d), 5.81 (1H, d), 6.44 (1H, d), 6.58 (1H, d), 7.31–7.33 (5H, m). δC (CDCl3) 3.34, 4.20, 9.30, 22.97, 24.99, 33.43, 43.04, 43.41, 44.01, 48.39, 52.24, 56.91, 59.85, 70.18, 80.85, 94.43, 116.41, 119.88, 125.72, 126.44, 126.84, 127.91, 128.18, 134.19, 136.89, 137.41, 143.32, 146.74. m/z found M+ for C30H33NO4, 471.2408; calculated 471.2410). Mp (HCl salt) 198–200 °C (dec, EtOH). Anal. (C30H34ClNO4·1.5H2O) C, H, N, Cl.

(1′R,5α,6R,7R,14α)-1′-(4,5-Epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-1′-(2-pyridyl)ethan-1′-ol (6)

2-Bromopyridine (1.13 mmol) in dry Et2O was cooled to −78 °C under a nitrogen atmosphere. n-Butyllithium (1.13 mmol) was added dropwise and the mixture stirred for 10 min before adding N-CPM dihydronorthevinone (8a, 1 mmol) in dry THF. The reaction mixture was allowed to warm to room temperature and stirred for 20 h. After completion, the reaction mixture was quenched with saturated NH4Cl solution (aqueous) and extracted with EtOAc. Organic layer was washed with brine, dried (Na2SO4), and evaporated to yield crude product (10) that was purified by flash chromatography using MeOH/CH2Cl2 (0.5:99.5) (35%). White solid. 1H NMR (CDCl3) δ 0.08–0.11 (2H, m), 0.45–0.52 (2H, m), 0.81–0.86 (2H, m), 1.18–1.22 (2H, m), 1.57–1.73 (4H, m), 2.21–2.41 (8H, m), 2.61–2.70 (2H, m), 2.91 (1H, d, J = 18.24 Hz), 3.02 (1H, d), 3.36 (3H, s), 3.82 (3H, s), 4.36 (1H, s), 5.87 (1H, s), 6.47 (1H, d), 6.62 (1H, d), 7.10–7.12 (1H, m), 7.59–7.63 (2H, m), 8.47 (1H, d). This was 3-O-demethylated using general procedure A to give 6 as a white solid. 1H NMR (CDCl3) δ 0.08–0.11 (2H, m), 0.40–0.51 (2H, m), 0.80–0.88 (2H, m), 1.20–1.27 (2H, m), 1.62 (1H, d), 1.67 (3H, s), 2.02–2.41 (8H, m), 2.61 (1H, dd), 2.78 (1H, dt), 2.91 (1H, d), 3.02 (1H, d), 3.35 (3H, s), 4.39 (1H, s), 4.55 (1H, bd), 5.83 (1H, s), 6.43 (1H, d), 6.61 (1H, d), 7.10–7.14 (1H, m), 7.62–7.64 (2H, m), 8.48 (1H, d). 13C NMR, 400 MHz (CDCl3) δ 3.21, 4.33, 9.35, 16.42, 22.45, 28.39, 28.86, 29.92, 35.24, 35.65, 43.81, 46.78, 49.36, 52.28, 57.95, 59.89, 80.1, 97.70, 116.01, 119.37, 120.54, 121.55, 128.54, 132.45, 135.78. 136.93, 145.30, 147.32, 166.46. HRMS, m/z for (C30H36N2O4), [MH]+: calcd 489.2753, found 489.2821. Anal. (C30H36Cl2N2O4·3H2O) C, H, N.

N-Cyclopropylmethylnorisonepenthol (12b)

Aldehyde 11b (13) (5.0 g, 1.61 mmol) was treated with PhMgBr (THF solution) in toluene (20 mL) for 24 h at room temperature. The reaction was quenched with a saturated NH4Cl solution and extracted with Et2O to yield 12b (2.97 g, 50%) which was purified by silica gel chromatography. 1H NMR δH (CDCl3) 0.01–0.08 (2H, m), 0.45–0.53 (2H, m), 0.74–0.76 (1H, m), 1.36 (1H, dd), 3.07 (1H, d), 3.53 (1H, d), 3.72 (3H, s), 3.83 (3H, s), 4.62 (1H, d), 5.23 (1H, s), 5.52 (1H, d), 5.88 (1H, d), 6.49 (1H, d), 6.61 (1H, d), 7.31–7.34 (5H, m). δC (CDCl3) 3.39, 4.20, 9.34, 15.27, 23.03, 25.18, 33.64, 43.05, 43.95, 44.04, 48.20, 52.78, 56.65, 57.04, 59.93, 70.39, 80.73, 94.99, 113.47, 119.28, 125.81, 126.78, 128.16, 128.43, 134.46, 136.85, 141.87, 143.47, 148.30. Found M+ for C31H35NO4, 485.2566; calculated 485.2566

N-Cyclopropylmethylnornepenthol (14b)

Ketone 13b (27) (800 mg, 1.61 mmol) in THF (10 mL) was added dropwise to a solution of LiAlH4 (2.5 equiv) in THF (10 mL) at room temperature. The solution was allowed to stir for 16 h before quenching with a solution of Rochelle salt (10 mL). Extraction with Et2O yielded 14b (700 mg, 90%) which was purified by recrystallization, Rf (EtOAc–hexane, 1:1, 0.5% NH3) 0.48. NMR δH (CDCl3) 0.02–0.07 (2H, m), 0.37–0.45 (2H, m), 0.64–0.69 (1H, m), 3.03 (1H, d), 3.34 (1H, d), 3.83 (3H, s), 3.84 (3H, s), 4.34 (1H, d), 4.63 (1H, d), 5.37 (1H, s), 5.56 (1H, d), 6.04 (1H, d), 6.48 (1H, d), 6.62 (1H, d), 7.26–7.33 (5H, m). δC (CDCl3) 3.50, 3.91, 9.24, 22.95, 30.43, 33.17, 42.55, 43.77, 44.13, 47.46, 54.97, 56.82, 57.05, 59.87, 77.70, 84.56, 97.62, 113.83, 119.33, 124.62, 127.58, 128.07, 128.17, 128.35, 134.65, 137.72, 141.88, 141.96, 147.82. m/z found M+ for C31H35NO4, 485.2588; calculated 485.2566.

Supporting Information

ARTICLE SECTIONS
Jump To

Full experimental details. This material is available free of charge via the Internet at http://pubs.acs.org.

Terms & Conditions

Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

ARTICLE SECTIONS
Jump To
  • Corresponding Author
    • Stephen M. Husbands - Department of Pharmacy and Pharmacology, University of Bath, Bath, BA2 7AY, U.K.;  Email: [email protected]
  • Authors
    • Vinod Kumar - Department of Pharmacy and Pharmacology, University of Bath, Bath, BA2 7AY, U.K.
    • Irna E. Ridzwan - Department of Pharmacy and Pharmacology, University of Bath, Bath, BA2 7AY, U.K.
    • Konstantinos Grivas - School of Chemistry, University of Bristol, Bristol, BS8 1TS, U.K.
    • John W. Lewis - Department of Pharmacy and Pharmacology, University of Bath, Bath, BA2 7AY, U.K.
    • Mary J. Clark - Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, United States
    • Claire Meurice - Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, United States
    • Corina Jimenez-Gomez - Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, United States
    • Irina Pogozheva - College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States
    • Henry Mosberg - College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States
    • John R. Traynor - Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, United States
  • Notes
    The authors declare no competing financial interest.

Acknowledgment

ARTICLE SECTIONS
Jump To

This work was funded by the National Institutes of Health National Institute on Drug Abuse Grant DA07315 (S.M.H.) and DA03910 (H.M.)

Abbreviations Used

ARTICLE SECTIONS
Jump To
MOP

μ opioid

DOP

δ opioid

KOP

κ opioid

NOP

nociceptin opioid peptide

EKC

ethylketocyclazocine

N/OFQ

nociceptin/orphanin FQ

References

ARTICLE SECTIONS
Jump To

This article references 29 other publications.

  1. 1
    Lewis, J. W.; Husbands, S. M. The orvinols and related opioids—high affinity ligands with diverse efficacy profiles Curr. Pharm. Des. 2004, 10, 717– 732
    [Crossref], [PubMed], [CAS], Google Scholar
    1
    The orvinols and related opioids - high affinity ligands with diverse efficacy profiles
    Lewis, John W.; Husbands, Stephen M.
    Current Pharmaceutical Design (2004), 10 (7), 717-732CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)
    A review. The thevinols and orvinols derived from thebaine via the thebaine-methylvinyl ketone adduct (thevinone) were thoroughly investigated in the 1960's and 1970's by the Reckitt group. From this work a no. of important opioids emerged. Buprenorphine is a μ partial agonist, κ/δ-antagonist that is now used primarily in the treatment of heroin abuse and dependence though it was initially launched as an analgesic for the treatment of moderate to severe pain. Etorphine and dihydroetorphine are very potent μ agonists that have found application in veterinary and human medicine resp. Diprenorphine is primarily a μ antagonist though it also has some κ-partial agonist effects. It has high affinity for all types of opioid receptors and as a "universal" opioid ligand has been much in demand as a pharmacol. tool. It has also been converted into a [11C] version for use in Positron Emission Tomog. (PET) studies of brain function related to the opioid receptor system. More recent medicinal chem. investigations have been concerned with gaining a greater understanding of buprenorphine's unique opioid profile. This has involved the synthesis and evaluation of a no. of series of buprenorphine analogs in which the C20 t-Bu group has been constrained in a ring system. These studies have suggested that the methyls in the t-Bu group inhibit the conformational changes in the κ-receptor required for generation of an agonist response. Introduction of a 7α-cinnamoylaminomethyl group in place of the orvinol tertiary alc. function leads to selective irreversible μ antagonism.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhvFOktbk%253D&md5=62cd0ff1388a60a28a096692dd81c65c
  2. 2
    Bentley, K. W.; Hardy, D. G. Novel analgesics and molecular rearrangements in morphine-thebaine group. 3. Alcohols of 6,14-endo-ethenotetrahydrooripavine series and derived analogs of n-allylnormorphine and -norcodeine J. Am. Chem. Soc. 1967, 89, 3281– 3292
    [ACS Full Text ACS Full Text], Google Scholar
    There is no corresponding record for this reference.
  3. 3
    Bentley, K. W.; Hardy, D. G.; Meek, B. Novel analgesics and molecular rearrangements in morphine-thebaine group. 2. Alcohols derived from 6,14-endo-etheno- and 6,14-endo-ethanotetrahydrothebaine J. Am. Chem. Soc. 1967, 89, 3273– 3280
    [ACS Full Text ACS Full Text], Google Scholar
    There is no corresponding record for this reference.
  4. 4
    Lewis, J. W.; Bentley, K. W.; Cowan, A. Narcotic analgesics and antagonists Annu. Rev. Pharmacol. 1971, 11, 241– 270
    [Crossref], Google Scholar
    There is no corresponding record for this reference.
  5. 5
    Lewis, J. W. Buprenorphine: Medicinal Chemistry. In Buprenorphine: Combatting Drug Abuse with a Unique Opioid; Cowan, A.; Lewis, J. W., Eds.; Wiley-Liss, Inc.: New York, 1995; pp 3– 16.
    Google Scholar
    There is no corresponding record for this reference.
  6. 6
    Hans, G. H. Buprenorphine in the Treatment of Neuropathic Pain. In Research and Development of Opioid-Related Ligands; ACS Symposium Series, 1131; American Chemical Society: Washington, DC, 2013; pp 103– 123.
    [ACS Full Text ACS Full Text], Google Scholar
    There is no corresponding record for this reference.
  7. 7
    Mogali, S.; Comer, S. D. Treatment of Pain and Opioid Abuse. In Research and Development of Opioid-Related Ligands; ACS Symposium Series, 1131; American Chemical Society: Washington, DC, 2013; pp 39– 60.
    [ACS Full Text ACS Full Text], Google Scholar
    There is no corresponding record for this reference.
  8. 8
    Husbands, S. M. Buprenorphine and Related Orvinols. In Research and Development of Opioid-Related Ligands; ACS Symposium Series, 1131; American Chemical Society: Washington, DC, 2013; pp 127– 144.
    [ACS Full Text ACS Full Text], Google Scholar
    There is no corresponding record for this reference.
  9. 9
    Cowan, A. Buprenorphine: the basic pharmacology revisited J. Addict. Med. 2007, 1, 68– 72
    [Crossref], [CAS], Google Scholar
    9
    Buprenorphine: the basic pharmacology revisited
    Cowan, Alan
    Journal of Addiction Medicine (2007), 1 (2), 68-72CODEN: JAMOCZ; ISSN:1932-0620. (Lippincott Williams & Wilkins)
    A review. The historical background leading to the current use of buprenorphine as an analgesic and its role in the management of opioid dependence is summarized. The popular description of buprenorphine as a "partial agonist" is discussed in relation to efficacy in animal models of antinociception and clin. analgesia. The latest information on the respiratory depressant effects of buprenorphine and its N-dealkylated metabolite (norbuprenorphine) is presented. New data on the buprenorphine withdrawal syndrome in rats are described.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXptlKisLw%253D&md5=87d7cfa1a9056a944983ef2b64cfdfd8
  10. 10
    Lutfy, K.; Cowan, A. Buprenorphine: a unique drug with complex pharmacology Curr. Neuropharmacol. 2004, 2, 395– 402
    [Crossref], [PubMed], [CAS], Google Scholar
    10
    Buprenorphine: A unique drug with complex pharmacology
    Lutfy, Kabirullah; Cowan, Alan
    Current Neuropharmacology (2004), 2 (4), 395-402CODEN: CNUEAN; ISSN:1570-159X. (Bentham Science Publishers Ltd.)
    A review. Buprenorphine, an opioid with mixed agonist-antagonist activity at classical opioid receptors, has been approved recently for the treatment of opioid dependency. Buprenorphine is also used as an analgesic. The buprenorphine dose-response curve is sometimes submaximal, or even bell-shaped, in nociceptive assays, depending upon the nature and intensity of the noxious stimulus. Moreover, buprenorphine, when administered with full agonists, such as morphine, antagonizes the action of these drugs. Partial agonism at the mu opioid receptor and, in some cases, antagonism at the kappa or delta opioid receptor have been considered as possible underlying mechanisms for the ceiling effect and bell-shaped dose-response curve of buprenorphine. While ceiling effects can be explained by the partial agonist activity of buprenorphine, the bell-shaped dose-response curve cannot be a consequence of this property of the drug. Recently, buprenorphine has been shown to activate the opioid receptor-like (ORL-1; also known as NOP) receptor. Supraspinal activation of the ORL-1 receptor counteracts the antinociceptive and rewarding actions of morphine, raising the possibility that these actions of buprenorphine can also be altered by its ability to concomitantly activate the ORL-1 receptor. The use of mol. biol. techniques has advanced the knowledge regarding the role of opioid receptors in modulation of pain and reward. In particular, generation of opioid receptor knockout mice has proven useful in this regard. Indeed, using knockout mice, the authors have recently shown that the antinociceptive effect of buprenorphine mediated primarily by the mu opioid receptor is attenuated by the ability of the drug to activate the ORL-1 receptor. Thus, the goal of this review is to provide evidence demonstrating that the ORL-1 receptor plays a functional role not only in the antinociceptive effect of buprenorphine but also in other actions of the drug as well.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXnvFejtbg%253D&md5=1771d5a23a42e2ff5347fb7270a2853e
  11. 11
    Budd, K.; Raffa, R. B. Buprenorphine: The Unique Opioid Analgesic: Pharmacology and Clinical Application; Georg Thieme: Berlin, 2005; p 134.
    [Crossref], Google Scholar
    There is no corresponding record for this reference.
  12. 12
    Lewis, J. W. Ring C-bridged derivatives of thebaine and oripavine Adv. Biochem. Psychopharmacol. 1973, 8, 123– 136
    [PubMed], [CAS], Google Scholar
    12
    Ring C-bridged derivatives of thebaine and oripavine
    Lewis, John W.
    Advances in Biochemical Psychopharmacology (1973), 8 (), 123-36CODEN: ABPYBL; ISSN:0065-2229.
    A review of the synthesis and analgesic activity of several ring C-bridged derivs. of thebaine and oripavine with 29 refs.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2cXksFyjsLo%253D&md5=fef66c59c499cf9ca4e3bd62cbe11b31
  13. 13
    Greedy, B. M.; Bradbury, F.; Thomas, M. P.; Grivas, K.; Cami-Kobeci, G.; Archambeau, A.; Bosse, K.; Clark, M. J.; Aceto, M.; Lewis, J. W.; Traynor, J. R.; Husbands, S. M. Orvinols with mixed kappa/mu opioid receptor agonist activity J. Med. Chem. 2013, 56, 3207– 3216
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    13
    Orvinols with Mixed Kappa/Mu Opioid Receptor Agonist Activity
    Greedy, Benjamin M.; Bradbury, Faye; Thomas, Mark P.; Grivas, Konstantinos; Cami-Kobeci, Gerta; Archambeau, Ashley; Bosse, Kelly; Clark, Mary J.; Aceto, Mario; Lewis, John W.; Traynor, John R.; Husbands, Stephen M.
    Journal of Medicinal Chemistry (2013), 56 (8), 3207-3216CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Dual-acting kappa opioid receptor (KOR) agonist and mu opioid receptor (MOR) partial agonist ligands have been put forward as potential treatment agents for cocaine and other psychostimulant abuse. Members of the orvinol series of ligands are known for their high binding affinity to both KOR and MOR, but efficacy at the individual receptors has not been thoroughly evaluated. In this study, it is shown that a predictive model for efficacy at KOR can be derived, with efficacy being controlled by the length of the group attached to C20 and by the introduction of branching into the side chain. In vivo evaluation of two ligands with the desired in vitro profile confirms both display KOR, and to a lesser extent MOR, activity in an analgesic assay suggesting that, in this series, in vitro measures of efficacy using the [35S]GTPγS assay are predictive of the in vivo profile.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjtVWrtbo%253D&md5=d692909a8c772cfa79f3c9697a9c64d1
  14. 14
    Anh, N. T.; Eisenstein, O. Theoretical interpretation of 1–2 asymmetric induction importance of anti-periplanarity Nouv. J. Chim. 1977, 1, 61– 70
    Google Scholar
    There is no corresponding record for this reference.
  15. 15
    Spagnolo, B.; Calo, G.; Polgar, W. E.; Jiang, F.; Olsen, C. M.; Berzetei-Gurske, I.; Khroyan, T. V.; Husbands, S. M.; Lewis, J. W.; Toll, L.; Zaveri, N. T. Activities of mixed NOP and mu-opioid receptor ligands Br. J. Pharmacol. 2008, 153, 609– 619
    [Crossref], [PubMed], [CAS], Google Scholar
    15
    Activities of mixed NOP and μ-opioid receptor ligands
    Spagnolo, B.; Calo, G.; Polgar, W. E.; Jiang, F.; Olsen, C. M.; Berzetei-Gurske, I.; Khroyan, T. V.; Husbands, S. M.; Lewis, J. W.; Toll, L.; Zaveri, N. T.
    British Journal of Pharmacology (2008), 153 (3), 609-619CODEN: BJPCBM; ISSN:0007-1188. (Nature Publishing Group)
    Compds. that activate both NOP and μ-opioid receptors might be useful as analgesics and drug abuse medications. Studies were carried out to better understand the biol. activity of such compds. Binding affinities were detd. on membranes from cells transfected with NOP and opioid receptors. Functional activity was detd. by [35S]GTPγS binding on cell membranes and using the mouse vas deferens prepn. in vitro and the tail flick antinociception assay in vivo. Compds. ranged in affinity from SR14150, 20-fold selective for NOP receptors, to buprenorphine, 50-fold selective for μ-opioid receptors. In the [35S]GTPγS assay, SR compds. ranged from full agonist to antagonist at NOP receptors and most were partial agonists at μ-opioid receptors. Buprenorphine was a low efficacy partial agonist at μ-opioid receptors, but did not stimulate [35S]GTPγS binding through NOP. In the mouse vas deferens, each compd., except for SR16430, inhibited elec. induced contractions. In each case, except for N/OFQ itself, the inhibition was due to μ-opioid receptor activation, as detd. by equiv. results in NOP receptor knockout tissues. SR14150 showed antinociceptive activity in the tail flick test, which was reversed by the opioid antagonist naloxone. Compds. that bind to both μ-opioid and NOP receptors have antinociceptive activity but the relative contribution of each receptor is unclear. These expts. help characterize compds. that bind to both receptors, to better understand the mechanism behind their biol. activities, and identify new pharmacol. tools to characterize NOP and opioid receptors.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhs1Kgsrg%253D&md5=6126762eb97b0a8db8d7a3ad82e026d3
  16. 16
    Lee, K. O.; Akil, H.; Woods, J. H.; Traynor, J. R. Differential binding properties of oripavines at cloned mu- and delta-opioid receptors Eur. J. Pharmacol. 1999, 378, 323– 330
    [Crossref], [PubMed], [CAS], Google Scholar
    16
    Differential binding properties of oripavines at cloned μ- and δ-opioid receptors
    Lee, Katherine O.; Akil, Huda; Woods, James H.; Traynor, John R.
    European Journal of Pharmacology (1999), 378 (3), 323-330CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier Science B.V.)
    This study examines the possibility that oripavine opioid receptor agonists bind equally to both high and low affinity states of the μ-opioid receptor. Studies were performed in C6 cells expressing μ- or δ-opioid receptors; high and low agonist affinity states of the receptors were defined by the absence and presence, resp. of Na+ ions and the GTP analog Gpp(NH)p. At the μ-opioid receptor dihydroetorphine and etorphine were full agonists, buprenorphine had moderate efficacy while diprenorphine was an antagonist. At the δ-opioid receptor, dihydroetorphine, etorphine, and diprenorphine had moderate efficacy while buprenorphine was an antagonist. The binding affinities of the oripavines at the μ-opioid receptor decreased only one to 2-fold in the presence of NaCl and Gpp(NH)p. In contrast, decreases in oripavine affinity at the δ-opioid receptor correlated with δ-opioid receptor efficacy. The ability of oripavine agonists to bind with high affinity to the low agonist affinity state of the ν-opioid receptor may explain the high potencies of these compds. in vivo.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXmtVKiuro%253D&md5=93c8030d6893f17fbbb98b3297e86bee
  17. 17
    Shaw, J. S.; Rourke, J. D.; Burns, K. M. Differential sensitivity of antinociceptive tests to opioid agonists and partial agonists Br. J. Pharmacol. 1988, 95, 578– 584
    [Crossref], [PubMed], [CAS], Google Scholar
    17
    Differential sensitivity of antinociceptive tests to opioid agonists and partial agonists
    Shaw, John S.; Rourke, Janet D.; Burns, Karen M.
    British Journal of Pharmacology (1988), 95 (2), 578-84CODEN: BJPCBM; ISSN:0007-1188.
    The antinociceptive activity of 16 opioid agonists and agonist-antagonist analgesics was detd. in mice by use of the hot plate and abdominal constriction (writhing) assays. Opioid agonists were approx. 10 times more effective in the abdominal constriction assay. The agonist-antagonists produced analgesia only in the abdominal constriction assay and antagonized the antinociceptive action of opioid agonists in the hot plate test. These differences were attributable to the different levels of stimulus employed in the 2 tests. By comparing the antagonist potencies of the agonist-antagonists in the hot plate test with their antinociceptive ED50 values in the abdominal constriction assay, an index of intrinsic activity was calcd.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXlvVentLY%253D&md5=c41ebb6cdb4cfad09706ce89ccb87aff
  18. 18
    Huang, P.; Kehner, G. B.; Cowan, A.; Liu-Chen, L. Y. Comparison of pharmacological activities of buprenorphine and norbuprenorphine: norbuprenorphine is a potent opioid agonist J. Pharmacol. Exp. Ther. 2001, 297, 688– 695
    [PubMed], [CAS], Google Scholar
    18
    Comparison of pharmacological activities of buprenorphine and norbuprenorphine: norbuprenorphine is a potent opioid agonist
    Huang, Peng; Kehner, George B.; Cowan, Alan; Liu-Chen, Lee-Yuan
    Journal of Pharmacology and Experimental Therapeutics (2001), 297 (2), 688-695CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)
    Buprenorphine (BUP) is an oripavine analgesic that is beneficial in the maintenance treatment of opiate-dependent individuals. Although BUP has been studied extensively, relatively little is known about norbuprenorphine (norBUP), a major dealkylated metabolite of BUP. The binding of norBUP to opioid and nociceptin/orphanin FQ (ORL1) receptors, and its effects on [35S]guanosine-5'-O-(γ-thio)triphosphate ([35S]GTPγS) binding mediated by opioid or ORL1 receptors and in the mouse acetic acid writhing test was described. Chinese hamster ovary cells stably transfected with each receptor were used for receptor binding and [35S]GTPγS binding. NorBUP exhibited high affinities for μ-, δ-, and κ-opioid receptors with Ki values in the nanomolar or subnanomolar range, comparable to those of BUP. NorBUP and BUP had low affinities for the ORL1 receptor with Ki values in the micromolar range. In the [35S]GTPγS binding assay, norBUP displayed characteristics distinct from BUP. At the δ-receptor, norBUP was a potent full agonist, yet BUP had no agonist activity and antagonized actions of norBUP and DPDPE. At μ- and κ-receptors, both norBUP and BUP were potent partial agonists, with norBUP having moderate efficacy and BUP having low efficacy. At the ORL1 receptor, norBUP was a full agonist with low potency, while BUP was a potent partial agonist. In the writhing test, BUP and norBUP both suppressed writhing in an efficacious and dose-dependent manner, giving A50 values of 0.067 and 0.21 mg/kg, s.c., resp. These results highlight the similarities and differences between BUP and norBUP, each of which may influence the unique pharmacol. profile of BUP.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXjt1WlsbY%253D&md5=18df8b467dfe6493aedf8d1d49a5592d
  19. 19
    Cami-Kobeci, G.; Polgar, W. E.; Khroyan, T. V.; Toll, L.; Husbands, S. M. Structural determinants of opioid and NOP receptor activity in derivatives of buprenorphine J. Med. Chem. 2011, 54, 6531– 6537
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    19
    Structural Determinants of Opioid and NOP Receptor Activity in Derivatives of Buprenorphine
    Cami-Kobeci, Gerta; Polgar, Willma E.; Khroyan, Taline V.; Toll, Lawrence; Husbands, Stephen M.
    Journal of Medicinal Chemistry (2011), 54 (19), 6531-6537CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    The unique pharmacol. profile of buprenorphine has led to its considerable success as an analgesic and as a treatment agent for drug abuse. Activation of nociceptin/orphanin FQ peptide (NOP) receptors has been postulated to account for certain aspects of buprenorphine's behavioral profile. In order to investigate the role of NOP activation further, a series of buprenorphine analogs has been synthesized with the aim of increasing affinity for the NOP receptor. Binding and functional assay data on these new compds. indicate that the area around C20 in the orvinols is key to NOP receptor activity, with several compds. displaying higher affinity than buprenorphine. One compd. was found to be a mu opioid receptor partial agonist of comparable efficacy to buprenorphine but with higher efficacy at NOP receptors.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFCgs7zN&md5=9e26145810991dca7f2b224326ac6d51
  20. 20
    Yu, G.; Yan, L.-D.; Li, Y.-L.; Wen, Q.; Dong, H.-J.; Gong, Z.-H. TH-030418: a potent long-acting opioid analgesic with low dependence liability Naunyn-Schmiedeberg’s Arch. Pharmacol. 2011, 384, 125– 131
    [Crossref], [PubMed], [CAS], Google Scholar
    20
    TH-030418: a potent long-acting opioid analgesic with low dependence liability
    Yu, Gang; Yan, Ling-Di; Li, Yu-Lei; Wen, Quan; Dong, Hua-Jin; Gong, Ze-Hui
    Naunyn-Schmiedeberg's Archives of Pharmacology (2011), 384 (2), 125-131CODEN: NSAPCC; ISSN:0028-1298. (Springer)
    Numerous efforts have been made on the chem. modification of opioid compds., with the ultimate goal of developing new opioid analgesics that is highly potent and low/non-addictive. In a search for such compds., TH-030418 [7α-[(R)-1-hydroxy-1-methyl-3-(thien-3-yl)-propyl]-6,14-endo-ethanotetrahydrooripavine] was synthesized. Here, we evaluated the pharmacol. activities of TH-030418, in comparison with morphine, the prototype opioid analgesic. In radioligand binding assays, TH-030418 bound potently and nonselectively to μ-, δ-, κ-, and ORL1 (opioid receptor-like 1) receptors stably expressed in CHO (Chinese hamster ovary) cells with K i values of 0.56, 0.73, 0.60, and 1.55 nM, resp. When administered s.c., TH-030418 was much more potent than morphine in analgesia, with the ED50 values of 1.37 μg/kg and 1.70 μg/kg in hot plate and acetic acid writhing tests, resp. The opioid antagonist naloxone blocked the antinociceptive effect of TH-030418, indicating that the action of TH-030418 was mediated by opioid receptors. The antinociceptive effect of s.c. TH-030418 in hot plate test lasted for more than 12 h, which is much longer than those of morphine (2.5 h) and dihydroetorphine (1.5 h). In addn., naloxone did not ppt. withdrawal syndrome in the mice treated with TH-030418 previously. Most importantly, TH-030418 did not induce conditioned place preference in mice after chronic treatment. These results indicate that TH-030418 is a potent long-acting opioid analgesic with low dependence liability and may be of some value in the development of new analgesics.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXpsFOksbY%253D&md5=da50c9cb062776d64c0a03a659b9ab29
  21. 21
    Anand, J. P.; Purington, L. C.; Pogozheva, I. D.; Traynor, J. R.; Mosberg, H. I. Modulation of opioid receptor ligand affinity and efficacy using active and inactive state receptor models Chem. Biol. Drug Des. 2012, 80, 763– 770
    [Crossref], [PubMed], [CAS], Google Scholar
    21
    Modulation of opioid receptor ligand affinity and efficacy using active and inactive state receptor models
    Anand, Jessica P.; Purington, Lauren C.; Pogozheva, Irina D.; Traynor, John R.; Mosberg, Henry I.
    Chemical Biology & Drug Design (2012), 80 (5), 763-770CODEN: CBDDAL; ISSN:1747-0277. (Wiley-Blackwell)
    Mu opioid receptor (MOR) agonists are widely used for the treatment of pain; however, chronic use results in the development of tolerance and dependence. It has been demonstrated that coadministration of a MOR agonist with a delta opioid receptor (DOR) antagonist maintains the analgesia assocd. with MOR agonists, but with reduced neg. side-effects. Using our newly refined opioid receptor models for structure-based ligand design, we have synthesized several pentapeptides with tailored affinity and efficacy profiles. In particular, we have obtained pentapeptides 8, Tyr-c(S-S)[DCys-1Nal-Nle-Cys]NH2, and 12, Tyr-c(S-S)[DCys-1Nal-Nle-Cys]OH, which demonstrates high affinity and full agonist behavior at MOR, high affinity but very low efficacy for DOR, and minimal affinity for the kappa opioid receptor (KOR). Functional properties of these peptides as MOR agonists/DOR antagonists lacking undesired KOR activity make them promising candidates for future in vivo studies of MOR/DOR interactions. Subtle structural variation of 12, by substituting D-Cys5 for L-Cys5, generated analog 13, which maintains low nanomolar MOR and DOR affinity, but which displays no efficacy at either receptor. These results demonstrate the power and utility of accurate receptor models for structure-based ligand design, as well as the profound sensitivity of ligand function on its structure.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFSmsL7E&md5=9ac4af2abaa46b7e03f19b31cce0a01b
  22. 22
    Wu, H.; Wacker, D.; Mileni, M.; Katritch, V.; Han, G. W.; Vardy, E.; Liu, W.; Thompson, A. A.; Huang, X.-P.; Carroll, F. I.; Mascarella, S. W.; Westkaemper, R. B.; Mosier, P. D.; Roth, B. L.; Cherezov, V.; Stevens, R. C. Structure of the human kappa-opioid receptor in complex with JDTic Nature 2012, 485, 327– 332
    [Crossref], [PubMed], [CAS], Google Scholar
    22
    Structure of the human κ-opioid receptor in complex with JDTic
    Wu, Huixian; Wacker, Daniel; Mileni, Mauro; Katritch, Vsevolod; Han, Gye Won; Vardy, Eyal; Liu, Wei; Thompson, Aaron A.; Huang, Xi-Ping; Carroll, F. Ivy; Mascarella, S. Wayne; Westkaemper, Richard B.; Mosier, Philip D.; Roth, Bryan L.; Cherezov, Vadim; Stevens, Raymond C.
    Nature (London, United Kingdom) (2012), 485 (7398), 327-332CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    Opioid receptors mediate the actions of endogenous and exogenous opioids on many physiol. processes, including the regulation of pain, respiratory drive, mood, and -in the case of κ-opioid receptor (κ-OR)- dysphoria and psychotomimesis. Here we report the crystal structure of the human κ-OR in complex with the selective antagonist JDTic, arranged in parallel dimers, at 2.9 Å resoln. The structure reveals important features of the ligand-binding pocket that contribute to the high affinity and subtype selectivity of JDTic for the human κ-OR. Modeling of other important κ-OR-selective ligands, including the morphinan-derived antagonists norbinaltorphimine and 5'-guanidinonaltrindole, and the diterpene agonist salvinorin A analog RB-64, reveals both common and distinct features for binding these diverse chemotypes. Anal. of site-directed mutagenesis and ligand structure-activity relationships confirms the interactions obsd. in the crystal structure, thereby providing a mol. explanation for κ-OR subtype selectivity, and essential insights for the design of compds. with new pharmacol. properties targeting the human κ-OR.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XksVegt7k%253D&md5=c54dd24df9065ed3b1a51420e74e2542
  23. 23
    Pogozheva, I. D.; Przydzial, M. J.; Mosberg, H. I. Homology modeling of opioid receptor–ligand complexes using experimental constraints AAPS J. 2005, 7, E434– 448
    [Crossref], Google Scholar
    There is no corresponding record for this reference.
  24. 24
    Husbands, S. M.; Lewis, J. W. Structural determinants of efficacy for kappa opioid receptors in the orvinol series: 7,7-spiro analogues of buprenorphine J. Med. Chem. 2000, 43, 139– 141
    [ACS Full Text ACS Full Text], Google Scholar
    There is no corresponding record for this reference.
  25. 25
    Coop, A.; Norton, C. L.; Berzetei-Gurske, I.; Burnside, J.; Toll, L.; Husbands, S. M.; Lewis, J. W. Structural determinants of opioid activity in the orvinols and related structures: ethers of orvinol and isoorvinol J. Med. Chem. 2000, 43, 1852– 1857
    [ACS Full Text ACS Full Text], Google Scholar
    There is no corresponding record for this reference.
  26. 26
    Hutchins, C. W.; Rapoport, H. Analgesics of the orvinol type 19-deoxy and 6,20-epoxy derivatives J. Med. Chem. 1984, 27, 521– 527
    [ACS Full Text ACS Full Text], Google Scholar
    There is no corresponding record for this reference.
  27. 27
    Marton, J.; Simon, C.; Hosztafi, S.; Szabó, Z.; Márki, Á.; Borsodi, A.; Makleit, S. New nepenthone and thevinone derivatives Bioorg. Med. Chem. 1997, 5, 369– 382
    [Crossref], Google Scholar
    There is no corresponding record for this reference.
  28. 28
    Broadbear, J. H.; Sumpter, T. L.; Burke, T. F.; Husbands, S. M.; Lewis, J. W.; Woods, J. H.; Traynor, J. R. Methcinnamox is a potent, long-lasting and selective antagonist of morphine-mediated antinociception in the mouse: Comparison with clocinnamox, β-FNA and β-chlornaltrexamine Pharmacol. Exp. Ther. 2000, 294, 933– 940
    [PubMed], [CAS], Google Scholar
    28
    Methocinnamox is a potent, long-lasting, and selective antagonist of morphine-mediated antinociception in the mouse: comparison with clocinnamox, β-funaltrexamine, and β-chlornaltrexamine
    Broadbear, Jillian H.; Sumpter, Tina L.; Burke, Timothy F.; Husbands, Stephen M.; Lewis, John W.; Woods, James H.; Traynor, John R.
    Journal of Pharmacology and Experimental Therapeutics (2000), 294 (3), 933-940CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)
    The irreversible μ-opioid antagonists β-funaltrexamine (β-FNA) and β-chlornaltrexamine (β-CNA) are important pharmacol. tools but have a κ-agonist activity and, in the latter case, low selectivity. This work examines whether clocinnamox (C-CAM) and the newer analog, methocinnamox (M-CAM), represent improved long-lasting antagonists for examg. μ-opioid-mediated effects in vivo. β-FNA, β-CNA, C-CAM, and M-CAM were compared after systemic administration in mice and in vitro. β-FNA and β-CNA were effective agonists in the writhing assay, reversible by the κ-antagonist norbinaltorphimine. Neither C-CAM nor M-CAM had agonist activity in vivo. M-CAM was devoid of agonist action at cloned opioid receptors. All four compds. depressed the dose-effect curve for the μ-agonist morphine in the warm-water tail-withdrawal test 1 h after administration; at 48 h, recovery was evident. In the writhing assay, the dose-effect curve for morphine was shifted in a parallel fashion in the order M-CAM » C-CAM > β-CNA ≥ β-FNA. In comparison with their ability to shift the dose-effect curve for bremazocine (κ) and BW373U86 (δ), β-CNA was the least μ-selective, followed by C-CAM < β-FNA < M-CAM. M-CAM (1.8 mg/kg) produced a 74-fold increase in the ED50 of morphine while showing no effect on bremazocine or BW373U86 dose-response curves. In binding assays, C-CAM and M-CAM were 8-fold selective for μ- over κ-receptors, whereas β-FNA and β-CNA were μ/δ-, but not μ/κ, selective. However, ex vivo binding assays confirmed the μ-receptor selectivity of M-CAM. M-CAM is thus a potent, long-lasting, and specific antagonist at μ-receptors in vivo that lacks confounding agonist actions.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXmtFCntr0%253D&md5=e140bc1fd679a4646ebbadf696bfc9fe
  29. 29
    Jutkiewicz, E. M.; Wood, S. K.; Houshyar, H.; Hsin, L.-W.; Rice, K. C.; Woods, J. H. The effects of CRF antagonists, antalarmin, CP154,526, LWH234, and R121919, in the forced swim test and on swim-induced increases in adrenocorticotropin in rats Psychopharmacol. 2005, 215– 223
    [Crossref], [CAS], Google Scholar
    29
    The effects of CRF antagonists, antalarmin, CP154,526, LWH234, and R121919, in the forced swim test and on swim-induced increases in adrenocorticotropin in rats
    Jutkiewicz, Emily M.; Wood, Susan K.; Houshyar, Hani; Hsin, Ling-Wei; Rice, Kenner C.; Woods, James H.
    Psychopharmacology (Berlin, Germany) (2005), 180 (2), 215-223CODEN: PSCHDL; ISSN:0033-3158. (Springer GmbH)
    Rationale Exposure to extreme stress has been suggested to produce long-term, detrimental alterations in the hypothalamic-pituitary-adrenal (HPA) axis leading to the development of mental disorders such as depression. Therefore, compds. that block the effects of stress hormones were investigated as potential therapeutics for depression. In the present study, we compared the potential antidepressant-like effects of four CRF antagonists, antalarmin, CP154,526, R121919, and LWH234 (at 3, 10, and 30 mg/kg i.p., 60 min prior to the forced swim test) and the corresponding effect on swim-induced HPA activation to better elucidate the relation between HPA activity and antidepressant activity. The antidepressant-like effects of the CRF antagonists and known antidepressants were detd. in the rat forced swim test, and blood samples were obtained before and after swimming for the evaluation of ACTH-releasing hormone (ACTH) levels. Antalarmin, CP154,526, and R121919 did not produce antidepressant-like effects in the forced swim test although these compds. decreased swim-induced increases in ACTH to various extents. In contrast, LWH234 reduced immobility in the forced swim test, without altering the swim-stress-induced ACTH response. However, this compd. antagonized restraint-induced ACTH release. These data suggest that reducing stress-induced increases in HPA activity alone may not be sufficient to produce antidepressant-like activity; however, redns. in HPA activity may contribute to antidepressant actions of some treatments. In addn., it is proposed that CRF antagonists may alter differentially the HPA axis depending on the type of stressor used or behavioral measure evaluated.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXltVKntr4%253D&md5=0b37777406cb47587c47ef8eecec69d0

Cited By

This article is cited by 18 publications.

  1. Alex Disney, Keith M. Olson, Amanda M. Shafer, Sierra C. Moore, Jessica P. Anand, John R. Traynor, Stephen M. Husbands. Opioid Antagonists from the Orvinol Series as Potential Reversal Agents for Opioid Overdose. ACS Chemical Neuroscience 2022, 13 (21) , 3108-3117. https://doi.org/10.1021/acschemneuro.2c00464
  2. Linghui Kong, Xuelian Shu, Siyuan Tang, Rongrong Ye, Huijiao Sun, Shuang Jiang, Zixiang Li, Jingrui Chai, Yun Fang, Yinjie Lan, Linqian Yu, Qiong Xie, Wei Fu, Yujun Wang, Wei Li, Zhuibai Qiu, Jinggen Liu, Liming Shao. SLL-627 Is a Highly Selective and Potent κ Opioid Receptor (KOR) Agonist with an Unexpected Nonreduction in Locomotor Activity. Journal of Medicinal Chemistry 2022, 65 (15) , 10377-10392. https://doi.org/10.1021/acs.jmedchem.2c00014
  3. Li Xiao, Yujun Wang, Mumei Zhang, Weiwei Wu, Linghui Kong, Yan Ma, Xuejun Xu, Xiao Liu, Qian He, Yuanyuan Qian, Huijiao Sun, Haihao Wu, Cheng Lin, Huoming Huang, Rongrong Ye, Shuang Jiang, Ru-Feng Ye, Congmin Yuan, Shengyang Fang, Dengqi Xue, Xicheng Yang, Hao Chen, Yilin Zheng, Linqian Yu, Qiong Xie, Lan Zheng, Wei Fu, Wei Li, Zhuibai Qiu, Jinggen Liu, Liming Shao. Discovery of a Highly Selective and Potent κ Opioid Receptor Agonist from N-Cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaines with Reduced Central Nervous System (CNS) Side Effects Navigated by the Message–Address Concept. Journal of Medicinal Chemistry 2019, 62 (24) , 11054-11070. https://doi.org/10.1021/acs.jmedchem.9b00857
  4. Juan Pablo Cueva, Christopher Roche, Mehrnoosh Ostovar, Vinod Kumar, Mary J. Clark, Todd M. Hillhouse, John W. Lewis, John R. Traynor, and Stephen M. Husbands . C7β-Methyl Analogues of the Orvinols: The Discovery of Kappa Opioid Antagonists with Nociceptin/Orphanin FQ Peptide (NOP) Receptor Partial Agonism and Low, or Zero, Efficacy at Mu Opioid Receptors. Journal of Medicinal Chemistry 2015, 58 (10) , 4242-4249. https://doi.org/10.1021/acs.jmedchem.5b00130
  5. Irina V. Sandulenko, Ekaterina S. Kovaleva, Maria V. Zelentsova, Asmik A. Ambartsumyan, Sergey N. Gorlov, Anastasia A. Danshina, Rinat R. Aysin, Sergey K. Moiseev. Control of the diastereoselectivity at C(20) in the formation of C(21)-fluorinated thevinols. Organic & Biomolecular Chemistry 2023, 21 (7) , 1440-1449. https://doi.org/10.1039/D2OB02144G
  6. Hannah B. Elam, Jennifer J. Donegan, Jenny Hsieh, Daniel J. Lodge. Gestational Buprenorphine Exposure Disrupts Dopamine Neuron Activity and Related Behaviors in Adulthood. eneuro 2022, 9 (4) , ENEURO.0499-21.2022. https://doi.org/10.1523/ENEURO.0499-21.2022
  7. Vanesa Nieto-Estévez, Jennifer J. Donegan, Courtney L. McMahon, Hannah B. Elam, Teresa A. Chavera, Parul Varma, Kelly A. Berg, Daniel J. Lodge, Jenny Hsieh. Buprenorphine Exposure Alters the Development and Migration of Interneurons in the Cortex. Frontiers in Molecular Neuroscience 2022, 15 https://doi.org/10.3389/fnmol.2022.889922
  8. János Marton, Anikó Fekete, Paul Cumming, Sándor Hosztafi, Pál Mikecz, Gjermund Henriksen. Diels–Alder Adducts of Morphinan-6,8-Dienes and Their Transformations. Molecules 2022, 27 (9) , 2863. https://doi.org/10.3390/molecules27092863
  9. Anastasija O. Finke, Marina Y. Ravaeva, Vyacheslav I. Krasnov, Igor V. Cheretaev, Elena N. Chuyan, Dmitry S. Baev, Elvira E. Shults. Cross‐Coupling‐Cyclocondensation Reaction Sequence to Access a Library of Ring‐C Bridged Pyrimidino‐tetrahydrothebaines and Pyrimidinotetrahydrooripavines. ChemistrySelect 2021, 6 (29) , 7391-7397. https://doi.org/10.1002/slct.202101790
  10. Norikazu Kiguchi, Huiping Ding, Shiroh Kishioka, Mei-Chuan Ko. Nociceptin/Orphanin FQ Peptide Receptor-Related Ligands as Novel Analgesics. Current Topics in Medicinal Chemistry 2020, 20 (31) , 2878-2888. https://doi.org/10.2174/1568026620666200508082615
  11. Irina V. Sandulenko, Asmik A. Ambartsumyan, Sergey K. Moiseev. Fluorinated and [ 18 F]fluorinated morphinan based opioid ligands. Organic & Biomolecular Chemistry 2020, 18 (29) , 5533-5557. https://doi.org/10.1039/D0OB00619J
  12. Edina Szűcs, János Marton, Zoltán Szabó, Sándor Hosztafi, Gabriella Kékesi, Gábor Tuboly, László Bánki, Gyöngyi Horváth, Pál T. Szabó, Csaba Tömböly, Zsuzsanna Katalin Varga, Sándor Benyhe, Ferenc Ötvös. Synthesis, biochemical, pharmacological characterization and in silico profile modelling of highly potent opioid orvinol and thevinol derivatives. European Journal of Medicinal Chemistry 2020, 191 , 112145. https://doi.org/10.1016/j.ejmech.2020.112145
  13. Keith M. Olson, David I. Duron, Daniel Womer, Ryan Fell, John M. Streicher, . Comprehensive molecular pharmacology screening reveals potential new receptor interactions for clinically relevant opioids. PLOS ONE 2019, 14 (6) , e0217371. https://doi.org/10.1371/journal.pone.0217371
  14. Jessica P. Anand, Deanna Montgomery. Multifunctional Opioid Ligands. 2018, 21-51. https://doi.org/10.1007/164_2018_104
  15. M.B. Zubair Khalid, Gangaram Pallikonda, R.N. Prasad Tulichala, Manab Chakravarty. Oxy-Wittig reactions of 1-naphthyl(aryl)methylphosphonates: a new approach to naphthylarylketones. Tetrahedron 2016, 72 (17) , 2094-2101. https://doi.org/10.1016/j.tet.2016.02.053
  16. Norikazu Kiguchi, Huiping Ding, Mei-Chuan Ko. Central N/OFQ-NOP Receptor System in Pain Modulation. 2016, 217-243. https://doi.org/10.1016/bs.apha.2015.10.001
  17. Richard J. Bodnar. Endogenous opiates and behavior: 2014. Peptides 2016, 75 , 18-70. https://doi.org/10.1016/j.peptides.2015.10.009
  18. Chris P Bailey, Stephen M Husbands. Novel approaches for the treatment of psychostimulant and opioid abuse – focus on opioid receptor-based therapies. Expert Opinion on Drug Discovery 2014, 9 (11) , 1333-1344. https://doi.org/10.1517/17460441.2014.964203
Download PDF

  • Abstract

    High Resolution Image
    Download MS PowerPoint Slide

    Chart 1

    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 1

    Scheme 1. a

    High Resolution Image
    Download MS PowerPoint Slide

    Scheme aReagents and conditions: (i) RMgBr, THF, rt; (ii) 2-pyridyllithium or 4-pyridyllithium, Et2O, THF, −78 °C → rt; (iii) PrSNa, HMPA, 110 °C or L-selectride, THF, reflux.

    Scheme 2

    Scheme 2. a

    High Resolution Image
    Download MS PowerPoint Slide

    Scheme aReagents and conditions: (i) PhMgBr, THF, rt; (ii) (COCl)2, DMSO, DMSO, CH2Cl2, −78 °C; (iii) LiAlH4, ether; (iv) PrSNa, HMPA, 110 °C or L-selectride, THF, reflux.

    Figure 1

    Figure 1. Nucleophilic addition (a) without chelation and (b) with chelation control.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 2

    Figure 2. Antinociceptive effect using the hot-plate assay in mice of (A) morphine and (B) EKC in the absence and presence of 10 mg/kg 1d. 1d was given as a 30 min pretreatment. Morphine and EKC were administered by a cumulative dosing procedure by intraperitoneal (ip) and subcutaneous (sc) injections, respectively, as described. (28)1d was given ip. Vehicle is a 1:1:9 solution of ethanol, emulphor (oil), and sterile water. (29) Data represent the mean ± SEM from five to six mice.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 3

    Figure 3. (A) Lack of antinociceptive effect of 1d at 32 mg/kg in the acetic acid stretch assay in mice. (B) Buprenorphine is a full agonist in this assay. The assay was performed as described. (28) Separate groups of mice were used for each dose. Data represent the mean ± SEM from six mice. Vehicle is as in Figure 2. (∗∗∗) p < 0.001; (∗∗∗∗) p < 0.0001.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 4

    Figure 4. (a) Predicted binding mode for 1d and analogues (magenta) in the KOPr in comparison to the crystal structure ligand JDTic (green). (b) Chloro-substituted analogues of 1d and potential interactions with the KOPr.

    High Resolution Image
    Download MS PowerPoint Slide

  • References

    ARTICLE SECTIONS
    Jump To

    This article references 29 other publications.

    1. 1
      Lewis, J. W.; Husbands, S. M. The orvinols and related opioids—high affinity ligands with diverse efficacy profiles Curr. Pharm. Des. 2004, 10, 717– 732
      [Crossref], [PubMed], [CAS], Google Scholar
      1
      The orvinols and related opioids - high affinity ligands with diverse efficacy profiles
      Lewis, John W.; Husbands, Stephen M.
      Current Pharmaceutical Design (2004), 10 (7), 717-732CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)
      A review. The thevinols and orvinols derived from thebaine via the thebaine-methylvinyl ketone adduct (thevinone) were thoroughly investigated in the 1960's and 1970's by the Reckitt group. From this work a no. of important opioids emerged. Buprenorphine is a μ partial agonist, κ/δ-antagonist that is now used primarily in the treatment of heroin abuse and dependence though it was initially launched as an analgesic for the treatment of moderate to severe pain. Etorphine and dihydroetorphine are very potent μ agonists that have found application in veterinary and human medicine resp. Diprenorphine is primarily a μ antagonist though it also has some κ-partial agonist effects. It has high affinity for all types of opioid receptors and as a "universal" opioid ligand has been much in demand as a pharmacol. tool. It has also been converted into a [11C] version for use in Positron Emission Tomog. (PET) studies of brain function related to the opioid receptor system. More recent medicinal chem. investigations have been concerned with gaining a greater understanding of buprenorphine's unique opioid profile. This has involved the synthesis and evaluation of a no. of series of buprenorphine analogs in which the C20 t-Bu group has been constrained in a ring system. These studies have suggested that the methyls in the t-Bu group inhibit the conformational changes in the κ-receptor required for generation of an agonist response. Introduction of a 7α-cinnamoylaminomethyl group in place of the orvinol tertiary alc. function leads to selective irreversible μ antagonism.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhvFOktbk%253D&md5=62cd0ff1388a60a28a096692dd81c65c
    2. 2
      Bentley, K. W.; Hardy, D. G. Novel analgesics and molecular rearrangements in morphine-thebaine group. 3. Alcohols of 6,14-endo-ethenotetrahydrooripavine series and derived analogs of n-allylnormorphine and -norcodeine J. Am. Chem. Soc. 1967, 89, 3281– 3292
      [ACS Full Text ACS Full Text], Google Scholar
      There is no corresponding record for this reference.
    3. 3
      Bentley, K. W.; Hardy, D. G.; Meek, B. Novel analgesics and molecular rearrangements in morphine-thebaine group. 2. Alcohols derived from 6,14-endo-etheno- and 6,14-endo-ethanotetrahydrothebaine J. Am. Chem. Soc. 1967, 89, 3273– 3280
      [ACS Full Text ACS Full Text], Google Scholar
      There is no corresponding record for this reference.
    4. 4
      Lewis, J. W.; Bentley, K. W.; Cowan, A. Narcotic analgesics and antagonists Annu. Rev. Pharmacol. 1971, 11, 241– 270
      [Crossref], Google Scholar
      There is no corresponding record for this reference.
    5. 5
      Lewis, J. W. Buprenorphine: Medicinal Chemistry. In Buprenorphine: Combatting Drug Abuse with a Unique Opioid; Cowan, A.; Lewis, J. W., Eds.; Wiley-Liss, Inc.: New York, 1995; pp 3– 16.
      Google Scholar
      There is no corresponding record for this reference.
    6. 6
      Hans, G. H. Buprenorphine in the Treatment of Neuropathic Pain. In Research and Development of Opioid-Related Ligands; ACS Symposium Series, 1131; American Chemical Society: Washington, DC, 2013; pp 103– 123.
      [ACS Full Text ACS Full Text], Google Scholar
      There is no corresponding record for this reference.
    7. 7
      Mogali, S.; Comer, S. D. Treatment of Pain and Opioid Abuse. In Research and Development of Opioid-Related Ligands; ACS Symposium Series, 1131; American Chemical Society: Washington, DC, 2013; pp 39– 60.
      [ACS Full Text ACS Full Text], Google Scholar
      There is no corresponding record for this reference.
    8. 8
      Husbands, S. M. Buprenorphine and Related Orvinols. In Research and Development of Opioid-Related Ligands; ACS Symposium Series, 1131; American Chemical Society: Washington, DC, 2013; pp 127– 144.
      [ACS Full Text ACS Full Text], Google Scholar
      There is no corresponding record for this reference.
    9. 9
      Cowan, A. Buprenorphine: the basic pharmacology revisited J. Addict. Med. 2007, 1, 68– 72
      [Crossref], [CAS], Google Scholar
      9
      Buprenorphine: the basic pharmacology revisited
      Cowan, Alan
      Journal of Addiction Medicine (2007), 1 (2), 68-72CODEN: JAMOCZ; ISSN:1932-0620. (Lippincott Williams & Wilkins)
      A review. The historical background leading to the current use of buprenorphine as an analgesic and its role in the management of opioid dependence is summarized. The popular description of buprenorphine as a "partial agonist" is discussed in relation to efficacy in animal models of antinociception and clin. analgesia. The latest information on the respiratory depressant effects of buprenorphine and its N-dealkylated metabolite (norbuprenorphine) is presented. New data on the buprenorphine withdrawal syndrome in rats are described.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXptlKisLw%253D&md5=87d7cfa1a9056a944983ef2b64cfdfd8
    10. 10
      Lutfy, K.; Cowan, A. Buprenorphine: a unique drug with complex pharmacology Curr. Neuropharmacol. 2004, 2, 395– 402
      [Crossref], [PubMed], [CAS], Google Scholar
      10
      Buprenorphine: A unique drug with complex pharmacology
      Lutfy, Kabirullah; Cowan, Alan
      Current Neuropharmacology (2004), 2 (4), 395-402CODEN: CNUEAN; ISSN:1570-159X. (Bentham Science Publishers Ltd.)
      A review. Buprenorphine, an opioid with mixed agonist-antagonist activity at classical opioid receptors, has been approved recently for the treatment of opioid dependency. Buprenorphine is also used as an analgesic. The buprenorphine dose-response curve is sometimes submaximal, or even bell-shaped, in nociceptive assays, depending upon the nature and intensity of the noxious stimulus. Moreover, buprenorphine, when administered with full agonists, such as morphine, antagonizes the action of these drugs. Partial agonism at the mu opioid receptor and, in some cases, antagonism at the kappa or delta opioid receptor have been considered as possible underlying mechanisms for the ceiling effect and bell-shaped dose-response curve of buprenorphine. While ceiling effects can be explained by the partial agonist activity of buprenorphine, the bell-shaped dose-response curve cannot be a consequence of this property of the drug. Recently, buprenorphine has been shown to activate the opioid receptor-like (ORL-1; also known as NOP) receptor. Supraspinal activation of the ORL-1 receptor counteracts the antinociceptive and rewarding actions of morphine, raising the possibility that these actions of buprenorphine can also be altered by its ability to concomitantly activate the ORL-1 receptor. The use of mol. biol. techniques has advanced the knowledge regarding the role of opioid receptors in modulation of pain and reward. In particular, generation of opioid receptor knockout mice has proven useful in this regard. Indeed, using knockout mice, the authors have recently shown that the antinociceptive effect of buprenorphine mediated primarily by the mu opioid receptor is attenuated by the ability of the drug to activate the ORL-1 receptor. Thus, the goal of this review is to provide evidence demonstrating that the ORL-1 receptor plays a functional role not only in the antinociceptive effect of buprenorphine but also in other actions of the drug as well.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXnvFejtbg%253D&md5=1771d5a23a42e2ff5347fb7270a2853e
    11. 11
      Budd, K.; Raffa, R. B. Buprenorphine: The Unique Opioid Analgesic: Pharmacology and Clinical Application; Georg Thieme: Berlin, 2005; p 134.
      [Crossref], Google Scholar
      There is no corresponding record for this reference.
    12. 12
      Lewis, J. W. Ring C-bridged derivatives of thebaine and oripavine Adv. Biochem. Psychopharmacol. 1973, 8, 123– 136
      [PubMed], [CAS], Google Scholar
      12
      Ring C-bridged derivatives of thebaine and oripavine
      Lewis, John W.
      Advances in Biochemical Psychopharmacology (1973), 8 (), 123-36CODEN: ABPYBL; ISSN:0065-2229.
      A review of the synthesis and analgesic activity of several ring C-bridged derivs. of thebaine and oripavine with 29 refs.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2cXksFyjsLo%253D&md5=fef66c59c499cf9ca4e3bd62cbe11b31
    13. 13
      Greedy, B. M.; Bradbury, F.; Thomas, M. P.; Grivas, K.; Cami-Kobeci, G.; Archambeau, A.; Bosse, K.; Clark, M. J.; Aceto, M.; Lewis, J. W.; Traynor, J. R.; Husbands, S. M. Orvinols with mixed kappa/mu opioid receptor agonist activity J. Med. Chem. 2013, 56, 3207– 3216
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      13
      Orvinols with Mixed Kappa/Mu Opioid Receptor Agonist Activity
      Greedy, Benjamin M.; Bradbury, Faye; Thomas, Mark P.; Grivas, Konstantinos; Cami-Kobeci, Gerta; Archambeau, Ashley; Bosse, Kelly; Clark, Mary J.; Aceto, Mario; Lewis, John W.; Traynor, John R.; Husbands, Stephen M.
      Journal of Medicinal Chemistry (2013), 56 (8), 3207-3216CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Dual-acting kappa opioid receptor (KOR) agonist and mu opioid receptor (MOR) partial agonist ligands have been put forward as potential treatment agents for cocaine and other psychostimulant abuse. Members of the orvinol series of ligands are known for their high binding affinity to both KOR and MOR, but efficacy at the individual receptors has not been thoroughly evaluated. In this study, it is shown that a predictive model for efficacy at KOR can be derived, with efficacy being controlled by the length of the group attached to C20 and by the introduction of branching into the side chain. In vivo evaluation of two ligands with the desired in vitro profile confirms both display KOR, and to a lesser extent MOR, activity in an analgesic assay suggesting that, in this series, in vitro measures of efficacy using the [35S]GTPγS assay are predictive of the in vivo profile.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjtVWrtbo%253D&md5=d692909a8c772cfa79f3c9697a9c64d1
    14. 14
      Anh, N. T.; Eisenstein, O. Theoretical interpretation of 1–2 asymmetric induction importance of anti-periplanarity Nouv. J. Chim. 1977, 1, 61– 70
      Google Scholar
      There is no corresponding record for this reference.
    15. 15
      Spagnolo, B.; Calo, G.; Polgar, W. E.; Jiang, F.; Olsen, C. M.; Berzetei-Gurske, I.; Khroyan, T. V.; Husbands, S. M.; Lewis, J. W.; Toll, L.; Zaveri, N. T. Activities of mixed NOP and mu-opioid receptor ligands Br. J. Pharmacol. 2008, 153, 609– 619
      [Crossref], [PubMed], [CAS], Google Scholar
      15
      Activities of mixed NOP and μ-opioid receptor ligands
      Spagnolo, B.; Calo, G.; Polgar, W. E.; Jiang, F.; Olsen, C. M.; Berzetei-Gurske, I.; Khroyan, T. V.; Husbands, S. M.; Lewis, J. W.; Toll, L.; Zaveri, N. T.
      British Journal of Pharmacology (2008), 153 (3), 609-619CODEN: BJPCBM; ISSN:0007-1188. (Nature Publishing Group)
      Compds. that activate both NOP and μ-opioid receptors might be useful as analgesics and drug abuse medications. Studies were carried out to better understand the biol. activity of such compds. Binding affinities were detd. on membranes from cells transfected with NOP and opioid receptors. Functional activity was detd. by [35S]GTPγS binding on cell membranes and using the mouse vas deferens prepn. in vitro and the tail flick antinociception assay in vivo. Compds. ranged in affinity from SR14150, 20-fold selective for NOP receptors, to buprenorphine, 50-fold selective for μ-opioid receptors. In the [35S]GTPγS assay, SR compds. ranged from full agonist to antagonist at NOP receptors and most were partial agonists at μ-opioid receptors. Buprenorphine was a low efficacy partial agonist at μ-opioid receptors, but did not stimulate [35S]GTPγS binding through NOP. In the mouse vas deferens, each compd., except for SR16430, inhibited elec. induced contractions. In each case, except for N/OFQ itself, the inhibition was due to μ-opioid receptor activation, as detd. by equiv. results in NOP receptor knockout tissues. SR14150 showed antinociceptive activity in the tail flick test, which was reversed by the opioid antagonist naloxone. Compds. that bind to both μ-opioid and NOP receptors have antinociceptive activity but the relative contribution of each receptor is unclear. These expts. help characterize compds. that bind to both receptors, to better understand the mechanism behind their biol. activities, and identify new pharmacol. tools to characterize NOP and opioid receptors.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhs1Kgsrg%253D&md5=6126762eb97b0a8db8d7a3ad82e026d3
    16. 16
      Lee, K. O.; Akil, H.; Woods, J. H.; Traynor, J. R. Differential binding properties of oripavines at cloned mu- and delta-opioid receptors Eur. J. Pharmacol. 1999, 378, 323– 330
      [Crossref], [PubMed], [CAS], Google Scholar
      16
      Differential binding properties of oripavines at cloned μ- and δ-opioid receptors
      Lee, Katherine O.; Akil, Huda; Woods, James H.; Traynor, John R.
      European Journal of Pharmacology (1999), 378 (3), 323-330CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier Science B.V.)
      This study examines the possibility that oripavine opioid receptor agonists bind equally to both high and low affinity states of the μ-opioid receptor. Studies were performed in C6 cells expressing μ- or δ-opioid receptors; high and low agonist affinity states of the receptors were defined by the absence and presence, resp. of Na+ ions and the GTP analog Gpp(NH)p. At the μ-opioid receptor dihydroetorphine and etorphine were full agonists, buprenorphine had moderate efficacy while diprenorphine was an antagonist. At the δ-opioid receptor, dihydroetorphine, etorphine, and diprenorphine had moderate efficacy while buprenorphine was an antagonist. The binding affinities of the oripavines at the μ-opioid receptor decreased only one to 2-fold in the presence of NaCl and Gpp(NH)p. In contrast, decreases in oripavine affinity at the δ-opioid receptor correlated with δ-opioid receptor efficacy. The ability of oripavine agonists to bind with high affinity to the low agonist affinity state of the ν-opioid receptor may explain the high potencies of these compds. in vivo.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXmtVKiuro%253D&md5=93c8030d6893f17fbbb98b3297e86bee
    17. 17
      Shaw, J. S.; Rourke, J. D.; Burns, K. M. Differential sensitivity of antinociceptive tests to opioid agonists and partial agonists Br. J. Pharmacol. 1988, 95, 578– 584
      [Crossref], [PubMed], [CAS], Google Scholar
      17
      Differential sensitivity of antinociceptive tests to opioid agonists and partial agonists
      Shaw, John S.; Rourke, Janet D.; Burns, Karen M.
      British Journal of Pharmacology (1988), 95 (2), 578-84CODEN: BJPCBM; ISSN:0007-1188.
      The antinociceptive activity of 16 opioid agonists and agonist-antagonist analgesics was detd. in mice by use of the hot plate and abdominal constriction (writhing) assays. Opioid agonists were approx. 10 times more effective in the abdominal constriction assay. The agonist-antagonists produced analgesia only in the abdominal constriction assay and antagonized the antinociceptive action of opioid agonists in the hot plate test. These differences were attributable to the different levels of stimulus employed in the 2 tests. By comparing the antagonist potencies of the agonist-antagonists in the hot plate test with their antinociceptive ED50 values in the abdominal constriction assay, an index of intrinsic activity was calcd.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXlvVentLY%253D&md5=c41ebb6cdb4cfad09706ce89ccb87aff
    18. 18
      Huang, P.; Kehner, G. B.; Cowan, A.; Liu-Chen, L. Y. Comparison of pharmacological activities of buprenorphine and norbuprenorphine: norbuprenorphine is a potent opioid agonist J. Pharmacol. Exp. Ther. 2001, 297, 688– 695
      [PubMed], [CAS], Google Scholar
      18
      Comparison of pharmacological activities of buprenorphine and norbuprenorphine: norbuprenorphine is a potent opioid agonist
      Huang, Peng; Kehner, George B.; Cowan, Alan; Liu-Chen, Lee-Yuan
      Journal of Pharmacology and Experimental Therapeutics (2001), 297 (2), 688-695CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)
      Buprenorphine (BUP) is an oripavine analgesic that is beneficial in the maintenance treatment of opiate-dependent individuals. Although BUP has been studied extensively, relatively little is known about norbuprenorphine (norBUP), a major dealkylated metabolite of BUP. The binding of norBUP to opioid and nociceptin/orphanin FQ (ORL1) receptors, and its effects on [35S]guanosine-5'-O-(γ-thio)triphosphate ([35S]GTPγS) binding mediated by opioid or ORL1 receptors and in the mouse acetic acid writhing test was described. Chinese hamster ovary cells stably transfected with each receptor were used for receptor binding and [35S]GTPγS binding. NorBUP exhibited high affinities for μ-, δ-, and κ-opioid receptors with Ki values in the nanomolar or subnanomolar range, comparable to those of BUP. NorBUP and BUP had low affinities for the ORL1 receptor with Ki values in the micromolar range. In the [35S]GTPγS binding assay, norBUP displayed characteristics distinct from BUP. At the δ-receptor, norBUP was a potent full agonist, yet BUP had no agonist activity and antagonized actions of norBUP and DPDPE. At μ- and κ-receptors, both norBUP and BUP were potent partial agonists, with norBUP having moderate efficacy and BUP having low efficacy. At the ORL1 receptor, norBUP was a full agonist with low potency, while BUP was a potent partial agonist. In the writhing test, BUP and norBUP both suppressed writhing in an efficacious and dose-dependent manner, giving A50 values of 0.067 and 0.21 mg/kg, s.c., resp. These results highlight the similarities and differences between BUP and norBUP, each of which may influence the unique pharmacol. profile of BUP.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXjt1WlsbY%253D&md5=18df8b467dfe6493aedf8d1d49a5592d
    19. 19
      Cami-Kobeci, G.; Polgar, W. E.; Khroyan, T. V.; Toll, L.; Husbands, S. M. Structural determinants of opioid and NOP receptor activity in derivatives of buprenorphine J. Med. Chem. 2011, 54, 6531– 6537
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      19
      Structural Determinants of Opioid and NOP Receptor Activity in Derivatives of Buprenorphine
      Cami-Kobeci, Gerta; Polgar, Willma E.; Khroyan, Taline V.; Toll, Lawrence; Husbands, Stephen M.
      Journal of Medicinal Chemistry (2011), 54 (19), 6531-6537CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      The unique pharmacol. profile of buprenorphine has led to its considerable success as an analgesic and as a treatment agent for drug abuse. Activation of nociceptin/orphanin FQ peptide (NOP) receptors has been postulated to account for certain aspects of buprenorphine's behavioral profile. In order to investigate the role of NOP activation further, a series of buprenorphine analogs has been synthesized with the aim of increasing affinity for the NOP receptor. Binding and functional assay data on these new compds. indicate that the area around C20 in the orvinols is key to NOP receptor activity, with several compds. displaying higher affinity than buprenorphine. One compd. was found to be a mu opioid receptor partial agonist of comparable efficacy to buprenorphine but with higher efficacy at NOP receptors.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFCgs7zN&md5=9e26145810991dca7f2b224326ac6d51
    20. 20
      Yu, G.; Yan, L.-D.; Li, Y.-L.; Wen, Q.; Dong, H.-J.; Gong, Z.-H. TH-030418: a potent long-acting opioid analgesic with low dependence liability Naunyn-Schmiedeberg’s Arch. Pharmacol. 2011, 384, 125– 131
      [Crossref], [PubMed], [CAS], Google Scholar
      20
      TH-030418: a potent long-acting opioid analgesic with low dependence liability
      Yu, Gang; Yan, Ling-Di; Li, Yu-Lei; Wen, Quan; Dong, Hua-Jin; Gong, Ze-Hui
      Naunyn-Schmiedeberg's Archives of Pharmacology (2011), 384 (2), 125-131CODEN: NSAPCC; ISSN:0028-1298. (Springer)
      Numerous efforts have been made on the chem. modification of opioid compds., with the ultimate goal of developing new opioid analgesics that is highly potent and low/non-addictive. In a search for such compds., TH-030418 [7α-[(R)-1-hydroxy-1-methyl-3-(thien-3-yl)-propyl]-6,14-endo-ethanotetrahydrooripavine] was synthesized. Here, we evaluated the pharmacol. activities of TH-030418, in comparison with morphine, the prototype opioid analgesic. In radioligand binding assays, TH-030418 bound potently and nonselectively to μ-, δ-, κ-, and ORL1 (opioid receptor-like 1) receptors stably expressed in CHO (Chinese hamster ovary) cells with K i values of 0.56, 0.73, 0.60, and 1.55 nM, resp. When administered s.c., TH-030418 was much more potent than morphine in analgesia, with the ED50 values of 1.37 μg/kg and 1.70 μg/kg in hot plate and acetic acid writhing tests, resp. The opioid antagonist naloxone blocked the antinociceptive effect of TH-030418, indicating that the action of TH-030418 was mediated by opioid receptors. The antinociceptive effect of s.c. TH-030418 in hot plate test lasted for more than 12 h, which is much longer than those of morphine (2.5 h) and dihydroetorphine (1.5 h). In addn., naloxone did not ppt. withdrawal syndrome in the mice treated with TH-030418 previously. Most importantly, TH-030418 did not induce conditioned place preference in mice after chronic treatment. These results indicate that TH-030418 is a potent long-acting opioid analgesic with low dependence liability and may be of some value in the development of new analgesics.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXpsFOksbY%253D&md5=da50c9cb062776d64c0a03a659b9ab29
    21. 21
      Anand, J. P.; Purington, L. C.; Pogozheva, I. D.; Traynor, J. R.; Mosberg, H. I. Modulation of opioid receptor ligand affinity and efficacy using active and inactive state receptor models Chem. Biol. Drug Des. 2012, 80, 763– 770
      [Crossref], [PubMed], [CAS], Google Scholar
      21
      Modulation of opioid receptor ligand affinity and efficacy using active and inactive state receptor models
      Anand, Jessica P.; Purington, Lauren C.; Pogozheva, Irina D.; Traynor, John R.; Mosberg, Henry I.
      Chemical Biology & Drug Design (2012), 80 (5), 763-770CODEN: CBDDAL; ISSN:1747-0277. (Wiley-Blackwell)
      Mu opioid receptor (MOR) agonists are widely used for the treatment of pain; however, chronic use results in the development of tolerance and dependence. It has been demonstrated that coadministration of a MOR agonist with a delta opioid receptor (DOR) antagonist maintains the analgesia assocd. with MOR agonists, but with reduced neg. side-effects. Using our newly refined opioid receptor models for structure-based ligand design, we have synthesized several pentapeptides with tailored affinity and efficacy profiles. In particular, we have obtained pentapeptides 8, Tyr-c(S-S)[DCys-1Nal-Nle-Cys]NH2, and 12, Tyr-c(S-S)[DCys-1Nal-Nle-Cys]OH, which demonstrates high affinity and full agonist behavior at MOR, high affinity but very low efficacy for DOR, and minimal affinity for the kappa opioid receptor (KOR). Functional properties of these peptides as MOR agonists/DOR antagonists lacking undesired KOR activity make them promising candidates for future in vivo studies of MOR/DOR interactions. Subtle structural variation of 12, by substituting D-Cys5 for L-Cys5, generated analog 13, which maintains low nanomolar MOR and DOR affinity, but which displays no efficacy at either receptor. These results demonstrate the power and utility of accurate receptor models for structure-based ligand design, as well as the profound sensitivity of ligand function on its structure.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFSmsL7E&md5=9ac4af2abaa46b7e03f19b31cce0a01b
    22. 22
      Wu, H.; Wacker, D.; Mileni, M.; Katritch, V.; Han, G. W.; Vardy, E.; Liu, W.; Thompson, A. A.; Huang, X.-P.; Carroll, F. I.; Mascarella, S. W.; Westkaemper, R. B.; Mosier, P. D.; Roth, B. L.; Cherezov, V.; Stevens, R. C. Structure of the human kappa-opioid receptor in complex with JDTic Nature 2012, 485, 327– 332
      [Crossref], [PubMed], [CAS], Google Scholar
      22
      Structure of the human κ-opioid receptor in complex with JDTic
      Wu, Huixian; Wacker, Daniel; Mileni, Mauro; Katritch, Vsevolod; Han, Gye Won; Vardy, Eyal; Liu, Wei; Thompson, Aaron A.; Huang, Xi-Ping; Carroll, F. Ivy; Mascarella, S. Wayne; Westkaemper, Richard B.; Mosier, Philip D.; Roth, Bryan L.; Cherezov, Vadim; Stevens, Raymond C.
      Nature (London, United Kingdom) (2012), 485 (7398), 327-332CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      Opioid receptors mediate the actions of endogenous and exogenous opioids on many physiol. processes, including the regulation of pain, respiratory drive, mood, and -in the case of κ-opioid receptor (κ-OR)- dysphoria and psychotomimesis. Here we report the crystal structure of the human κ-OR in complex with the selective antagonist JDTic, arranged in parallel dimers, at 2.9 Å resoln. The structure reveals important features of the ligand-binding pocket that contribute to the high affinity and subtype selectivity of JDTic for the human κ-OR. Modeling of other important κ-OR-selective ligands, including the morphinan-derived antagonists norbinaltorphimine and 5'-guanidinonaltrindole, and the diterpene agonist salvinorin A analog RB-64, reveals both common and distinct features for binding these diverse chemotypes. Anal. of site-directed mutagenesis and ligand structure-activity relationships confirms the interactions obsd. in the crystal structure, thereby providing a mol. explanation for κ-OR subtype selectivity, and essential insights for the design of compds. with new pharmacol. properties targeting the human κ-OR.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XksVegt7k%253D&md5=c54dd24df9065ed3b1a51420e74e2542
    23. 23
      Pogozheva, I. D.; Przydzial, M. J.; Mosberg, H. I. Homology modeling of opioid receptor–ligand complexes using experimental constraints AAPS J. 2005, 7, E434– 448
      [Crossref], Google Scholar
      There is no corresponding record for this reference.
    24. 24
      Husbands, S. M.; Lewis, J. W. Structural determinants of efficacy for kappa opioid receptors in the orvinol series: 7,7-spiro analogues of buprenorphine J. Med. Chem. 2000, 43, 139– 141
      [ACS Full Text ACS Full Text], Google Scholar
      There is no corresponding record for this reference.
    25. 25
      Coop, A.; Norton, C. L.; Berzetei-Gurske, I.; Burnside, J.; Toll, L.; Husbands, S. M.; Lewis, J. W. Structural determinants of opioid activity in the orvinols and related structures: ethers of orvinol and isoorvinol J. Med. Chem. 2000, 43, 1852– 1857
      [ACS Full Text ACS Full Text], Google Scholar
      There is no corresponding record for this reference.
    26. 26
      Hutchins, C. W.; Rapoport, H. Analgesics of the orvinol type 19-deoxy and 6,20-epoxy derivatives J. Med. Chem. 1984, 27, 521– 527
      [ACS Full Text ACS Full Text], Google Scholar
      There is no corresponding record for this reference.
    27. 27
      Marton, J.; Simon, C.; Hosztafi, S.; Szabó, Z.; Márki, Á.; Borsodi, A.; Makleit, S. New nepenthone and thevinone derivatives Bioorg. Med. Chem. 1997, 5, 369– 382
      [Crossref], Google Scholar
      There is no corresponding record for this reference.
    28. 28
      Broadbear, J. H.; Sumpter, T. L.; Burke, T. F.; Husbands, S. M.; Lewis, J. W.; Woods, J. H.; Traynor, J. R. Methcinnamox is a potent, long-lasting and selective antagonist of morphine-mediated antinociception in the mouse: Comparison with clocinnamox, β-FNA and β-chlornaltrexamine Pharmacol. Exp. Ther. 2000, 294, 933– 940
      [PubMed], [CAS], Google Scholar
      28
      Methocinnamox is a potent, long-lasting, and selective antagonist of morphine-mediated antinociception in the mouse: comparison with clocinnamox, β-funaltrexamine, and β-chlornaltrexamine
      Broadbear, Jillian H.; Sumpter, Tina L.; Burke, Timothy F.; Husbands, Stephen M.; Lewis, John W.; Woods, James H.; Traynor, John R.
      Journal of Pharmacology and Experimental Therapeutics (2000), 294 (3), 933-940CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)
      The irreversible μ-opioid antagonists β-funaltrexamine (β-FNA) and β-chlornaltrexamine (β-CNA) are important pharmacol. tools but have a κ-agonist activity and, in the latter case, low selectivity. This work examines whether clocinnamox (C-CAM) and the newer analog, methocinnamox (M-CAM), represent improved long-lasting antagonists for examg. μ-opioid-mediated effects in vivo. β-FNA, β-CNA, C-CAM, and M-CAM were compared after systemic administration in mice and in vitro. β-FNA and β-CNA were effective agonists in the writhing assay, reversible by the κ-antagonist norbinaltorphimine. Neither C-CAM nor M-CAM had agonist activity in vivo. M-CAM was devoid of agonist action at cloned opioid receptors. All four compds. depressed the dose-effect curve for the μ-agonist morphine in the warm-water tail-withdrawal test 1 h after administration; at 48 h, recovery was evident. In the writhing assay, the dose-effect curve for morphine was shifted in a parallel fashion in the order M-CAM » C-CAM > β-CNA ≥ β-FNA. In comparison with their ability to shift the dose-effect curve for bremazocine (κ) and BW373U86 (δ), β-CNA was the least μ-selective, followed by C-CAM < β-FNA < M-CAM. M-CAM (1.8 mg/kg) produced a 74-fold increase in the ED50 of morphine while showing no effect on bremazocine or BW373U86 dose-response curves. In binding assays, C-CAM and M-CAM were 8-fold selective for μ- over κ-receptors, whereas β-FNA and β-CNA were μ/δ-, but not μ/κ, selective. However, ex vivo binding assays confirmed the μ-receptor selectivity of M-CAM. M-CAM is thus a potent, long-lasting, and specific antagonist at μ-receptors in vivo that lacks confounding agonist actions.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXmtFCntr0%253D&md5=e140bc1fd679a4646ebbadf696bfc9fe
    29. 29
      Jutkiewicz, E. M.; Wood, S. K.; Houshyar, H.; Hsin, L.-W.; Rice, K. C.; Woods, J. H. The effects of CRF antagonists, antalarmin, CP154,526, LWH234, and R121919, in the forced swim test and on swim-induced increases in adrenocorticotropin in rats Psychopharmacol. 2005, 215– 223
      [Crossref], [CAS], Google Scholar
      29
      The effects of CRF antagonists, antalarmin, CP154,526, LWH234, and R121919, in the forced swim test and on swim-induced increases in adrenocorticotropin in rats
      Jutkiewicz, Emily M.; Wood, Susan K.; Houshyar, Hani; Hsin, Ling-Wei; Rice, Kenner C.; Woods, James H.
      Psychopharmacology (Berlin, Germany) (2005), 180 (2), 215-223CODEN: PSCHDL; ISSN:0033-3158. (Springer GmbH)
      Rationale Exposure to extreme stress has been suggested to produce long-term, detrimental alterations in the hypothalamic-pituitary-adrenal (HPA) axis leading to the development of mental disorders such as depression. Therefore, compds. that block the effects of stress hormones were investigated as potential therapeutics for depression. In the present study, we compared the potential antidepressant-like effects of four CRF antagonists, antalarmin, CP154,526, R121919, and LWH234 (at 3, 10, and 30 mg/kg i.p., 60 min prior to the forced swim test) and the corresponding effect on swim-induced HPA activation to better elucidate the relation between HPA activity and antidepressant activity. The antidepressant-like effects of the CRF antagonists and known antidepressants were detd. in the rat forced swim test, and blood samples were obtained before and after swimming for the evaluation of ACTH-releasing hormone (ACTH) levels. Antalarmin, CP154,526, and R121919 did not produce antidepressant-like effects in the forced swim test although these compds. decreased swim-induced increases in ACTH to various extents. In contrast, LWH234 reduced immobility in the forced swim test, without altering the swim-stress-induced ACTH response. However, this compd. antagonized restraint-induced ACTH release. These data suggest that reducing stress-induced increases in HPA activity alone may not be sufficient to produce antidepressant-like activity; however, redns. in HPA activity may contribute to antidepressant actions of some treatments. In addn., it is proposed that CRF antagonists may alter differentially the HPA axis depending on the type of stressor used or behavioral measure evaluated.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXltVKntr4%253D&md5=0b37777406cb47587c47ef8eecec69d0

  • Supporting Information

    Supporting Information

    ARTICLE SECTIONS
    Jump To

    Full experimental details. This material is available free of charge via the Internet at http://pubs.acs.org.


    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

PDF [ 3MB]

Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

You’ve supercharged your research process with ACS and Mendeley!

STEP 1:
Click to create an ACS ID

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

MENDELEY PAIRING EXPIRED
Your Mendeley pairing has expired. Please reconnect