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 [(35)S]GTPγS assay are predictive of the in vivo profile.
authors: Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK.
authors: Benjamin M
authors: BM
authors: Greedy
authors: Faye
authors: F
authors: Bradbury
authors: Mark P
authors: MP
authors: Thomas
authors: Konstantinos
authors: K
authors: Grivas
authors: Gerta
authors: G
authors: Cami-Kobeci
authors: Ashley
authors: A
authors: Archambeau
authors: Kelly
authors: K
authors: Bosse
authors: Mary J
authors: MJ
authors: Clark
authors: Mario
authors: M
authors: Aceto
authors: John W
authors: JW
authors: Lewis
authors: John R
authors: JR
authors: Traynor
authors: Stephen M
authors: SM
authors: Husbands
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000188:drug therapy*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D016244:Guanosine 5'-O-(3-Thiotriphosphate)