Orvinols with Mixed Kappa/Mu Opioid Receptor Agonist Activity

被引：37

作者：

Greedy, Benjamin M. ^{[1
]}

Bradbury, Faye ^{[2
]}

Thomas, Mark P. ^{[1
]}

Grivas, Konstantinos ^{[3
]}

Cami-Kobeci, Gerta ^{[1
]}

Archambeau, Ashley ^{[2
]}

Bosse, Kelly ^{[2
]}

Clark, Mary J. ^{[2
]}

Aceto, Mario ^{[4
]}

Lewis, John W. ^{[1
]}

Traynor, John R. ^{[2
]}

Husbands, Stephen M. ^{[1
]}

机构：

[1] Univ Bath, Dept Pharm & Pharmacol, Bath BA2 7AY, Avon, England

[2] Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA

[3] Univ Bristol, Sch Chem, Bristol BS8 1TS, Avon, England

[4] Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 08期

基金：

美国国家卫生研究院; 英国惠康基金;

关键词：

RHESUS-MONKEYS; STRUCTURAL DETERMINANTS; COCAINE; ANALOGS; BUPRENORPHINE; SENSITIZATION; DEPENDENCE; EFFICACY; MORPHINE; BINDING;

D O I：

10.1021/jm301543e

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 lay KOR, and to a lesser extent MOR, activity in an analgesic assay suggesting that, in this series, in vitro measures of efficacy using the [S-35]GTP gamma S assay are predictive of the in vivo profile.

引用

页码：3207 / 3216

页数：10

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