Methocinnamox is a potent, long-lasting, and selective antagonist of morphine-mediated antinociception in the mouse: Comparison with clocinnamox, beta-funaltrexamine, and beta-chlornaltrexamine

The irreversible mu-opioid antagonists beta-funaltrexamine (beta-FNA) and b eta-chlornaltrexamine (beta-CNA) are important pharmacological tools but ha ve a kappa-agonist activity and, in the latter case, low selectivity. This work examines whether clocinnamox (C-CAM) and the newer analog, methocinnam ox (M-CAM), represent improved long-lasting antagonists for examining mu-op ioid-mediated effects in vivo. beta-FNA, beta-CNA, C-CAM, and M-CAM were co mpared after systemic administration in mice and in vitro. beta-FNA and bet a-CNA were effective agonists in the writhing assay, reversible by the kapp a-antagonist norbinaltorphimine. Neither C-CAM nor M-CAM had agonist activi ty 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 morph ine 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 m orphine was shifted in a parallel fashion in the order M-CAM >> C-CAM > bet a-CNA greater than or equal to beta-FNA. In comparison with their ability t o 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 ED50 of morphine whil e showing no effect on bremazocine or BW373U86 dose-response curves. In bin ding assays, C-CAM and M-CAM were 8-fold selective for mu- over kappa-recep tors, whereas beta-FNA and beta-CNA were mu/delta-, but not mu/kappa select ive. 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.