Orvinols with mixed kappa/Mu opioid receptor agonist activity

Benjamin M. Greedy; Faye Bradbury; Mark P. Thomas; Konstantinos Grivas; Gerta Cami-Kobeci; Ashley Archambeau; Kelly Bosse; Mary J. Clark; Mario Aceto; John W. Lewis; John R. Traynor; Stephen M. Husbands

doi:10.1021/jm301543e

Orvinols with mixed kappa/Mu opioid receptor agonist activity

Benjamin M. Greedy, Faye Bradbury, Mark P. Thomas, Konstantinos Grivas, Gerta Cami-Kobeci, Ashley Archambeau, Kelly Bosse, Mary J. Clark, Mario Aceto, John W. Lewis, John R. Traynor, Stephen M. Husbands

Research output: Contribution to journal › Article › peer-review

35 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	3207-3216
Number of pages	10
Journal	Journal of Medicinal Chemistry
Volume	56
Issue number	8
Early online date	25 Feb 2013
DOIs	https://doi.org/10.1021/jm301543e
Publication status	Published - 25 Apr 2013

Access to Document

10.1021/jm301543eLicence: Other

Cite this

@article{4cabde2766c34a669470aeccfed1e154,

title = "Orvinols with mixed kappa/Mu opioid receptor agonist activity",

abstract = "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.",

author = "Greedy, {Benjamin M.} and Faye Bradbury and Thomas, {Mark P.} and Konstantinos Grivas and Gerta Cami-Kobeci and Ashley Archambeau and Kelly Bosse and Clark, {Mary J.} and Mario Aceto and Lewis, {John W.} and Traynor, {John R.} and Husbands, {Stephen M.}",

note = "{\textcopyright} 2013 American Chemical Society",

year = "2013",

month = apr,

day = "25",

doi = "10.1021/jm301543e",

language = "English",

volume = "56",

pages = "3207--3216",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society (ACS)",

number = "8",

}

TY - JOUR

T1 - Orvinols with mixed kappa/Mu opioid receptor agonist activity

AU - Greedy, Benjamin M.

AU - Bradbury, Faye

AU - Thomas, Mark P.

AU - Grivas, Konstantinos

AU - Cami-Kobeci, Gerta

AU - Archambeau, Ashley

AU - Bosse, Kelly

AU - Clark, Mary J.

AU - Aceto, Mario

AU - Lewis, John W.

AU - Traynor, John R.

AU - Husbands, Stephen M.

PY - 2013/4/25

Y1 - 2013/4/25

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84876823658&partnerID=8YFLogxK

U2 - 10.1021/jm301543e

DO - 10.1021/jm301543e

M3 - Article

C2 - 23438330

AN - SCOPUS:84876823658

SN - 0022-2623

VL - 56

SP - 3207

EP - 3216

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 8

ER -

Orvinols with mixed kappa/Mu opioid receptor agonist activity

Abstract

Access to Document

Other files and links

Fingerprint

Cite this