Vol. 294, Issue 3, 933-940, September 2000

Methocinnamox Is a Potent, Long-Lasting, and Selective Antagonist of Morphine-Mediated Antinociception in the Mouse: Comparison with Clocinnamox, -Funaltrexamine, and -Chlornaltrexamine¹

Jillian H. Broadbear, Tina L. Sumpter, Timothy F. Burke² , Stephen M Husbands³ , John W. Lewis, James H. Woods and John R. Traynor

Departments of Psychology (J.H.B., J.H.W.) and Pharmacology (J.R.T., T.F.B., J.H.W.), University of Michigan Medical School, Ann Arbor, Michigan; and Department of Chemistry, University of Bristol, Bristol, United Kingdom (S.M.H., J.W.L.)

The irreversible µ-opioid antagonists -funaltrexamine (-FNA) and -chlornaltrexamine (-CNA) are important pharmacological tools but have a -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 µ-opioid-mediated effects in vivo. -FNA, -CNA, C-CAM, and M-CAM were compared after systemic administration in mice and in vitro. -FNA and -CNA were effective agonists in the writhing assay, reversible by the -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 µ-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 > -CNA  -FNA. In comparison with their ability to shift the dose-effect curve for bremazocine () and BW373U86 (), -CNA was the least µ-selective, followed by C-CAM < -FNA < M-CAM. M-CAM (1.8 mg/kg) produced a 74-fold increase in the ED₅₀ 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 µ- over -receptors, whereas -FNA and -CNA were µ/-, but not µ/, selective. However, ex vivo binding assays confirmed the µ-receptor selectivity of M-CAM. M-CAM is thus a potent, long-lasting, and specific antagonist at µ-receptors in vivo that lacks confounding agonist actions.