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 journalArticlepeer-review

    35 Citations (Scopus)


    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 languageEnglish
    Pages (from-to)3207-3216
    Number of pages10
    JournalJournal of Medicinal Chemistry
    Issue number8
    Early online date25 Feb 2013
    Publication statusPublished - 25 Apr 2013


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