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J Med Chem. 2013 Apr 25;56(8):3207-16. doi: 10.1021/jm301543e. Epub 2013 Apr 3.

Orvinols with mixed kappa/mu opioid receptor agonist activity.

Author information

1
Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK.

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 [(35)S]GTPγS assay are predictive of the in vivo profile.

PMID:
23438330
PMCID:
PMC3646402
DOI:
10.1021/jm301543e
[Indexed for MEDLINE]
Free PMC Article

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