title: Methocinnamox is a potent, long-lasting, and selective antagonist of morphine-mediated antinociception in the mouse: comparison with clocinnamox, beta-funaltrexamine, and beta-chlornaltrexamine.
abstract: The irreversible mu-opioid antagonists beta-funaltrexamine (beta-FNA) and beta-chlornaltrexamine (beta-CNA) are important pharmacological tools but have a kappa-agonist activity and, in the latter case, low selectivity. This work examines whether clocinnamox (C-CAM) and the newer analog, methocinnamox (M-CAM), represent improved long-lasting antagonists for examining mu-opioid-mediated effects in vivo. beta-FNA, beta-CNA, C-CAM, and M-CAM were compared after systemic administration in mice and in vitro. beta-FNA and beta-CNA were effective agonists in the writhing assay, reversible by the kappa-antagonist norbinaltorphimine. Neither C-CAM nor M-CAM had agonist activity in vivo. M-CAM was devoid of agonist action at cloned opioid receptors. All four compounds depressed the dose-effect curve for the mu-agonist morphine in the warm-water tail-withdrawal test 1 h after administration; at 48 h, recovery was evident. In the writhing assay, the dose-effect curve for morphine was shifted in a parallel fashion in the order M-CAM >> C-CAM > beta-CNA > or = beta-FNA. In comparison with their ability to shift the dose-effect curve for bremazocine (kappa) and BW373U86 (delta), beta-CNA was the least mu-selective, followed by C-CAM < beta-FNA < M-CAM. M-CAM (1.8 mg/kg) produced a 74-fold increase in the ED(50) of morphine while showing no effect on bremazocine or BW373U86 dose-response curves. In binding assays, C-CAM and M-CAM were 8-fold selective for mu- over kappa-receptors, whereas beta-FNA and beta-CNA were mu/delta-, but not mu/kappa, selective. However, ex vivo binding assays confirmed the mu-receptor selectivity of M-CAM. M-CAM is thus a potent, long-lasting, and specific antagonist at mu-receptors in vivo that lacks confounding agonist actions.
authors.affiliation: Department of Psychology, University of Michigan Medical School, Ann Arbor 48109-0632, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Broadbear
authors.forename: T L
authors.initials: TL
authors.lastname: Sumpter
authors.forename: T F
authors.initials: TF
authors.lastname: Burke
authors.forename: S M
authors.initials: SM
authors.lastname: Husbands
authors.forename: J W
authors.initials: JW
authors.lastname: Lewis
authors.forename: J H
authors.initials: JH
authors.lastname: Woods
authors.forename: J R
authors.initials: JR
authors.lastname: Traynor
mesh_terms: D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D002934:Cinnamates / Q000378:metabolism / Q000494:pharmacology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009020:Morphine / Q000037:antagonists & inhibitors*; D009022:Morphine Derivatives / Q000378:metabolism / Q000494:pharmacology*; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000378:metabolism / Q000494:pharmacology*; D010147:Pain Measurement; D011869:Radioligand Assay; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D002934:Cinnamates; D009022:Morphine Derivatives; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C412891:methocinnamox; C076806:clocinnamox; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009271:Naltrexone; C017120:chlornaltrexamine; C024524:beta-funaltrexamine; D009020:Morphine