RT Journal Article SR Electronic T1 Development of Muscarinic Analgesics Derived from Epibatidine: Role of the M4 Receptor Subtype JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 1143 OP 1150 VO 288 IS 3 A1 James L. Ellis A1 Dean Harman A1 Javier Gonzalez A1 Michael L. Spera A1 Ronggang Liu A1 T. Y. Shen A1 Donna M. Wypij A1 Fangming Zuo YR 1999 UL http://jpet.aspetjournals.org/content/288/3/1143.abstract AB Epibatidine, a neurotoxin isolated from the skin of Epipedobates tricolor, is an efficacious antinociceptive agent with a potency 200 times that of morphine. The toxicity of epibatidine, because of its nonspecificity for both peripheral and central nicotinic receptors, precludes its development as an analgesic. During the synthesis of epibatidine analogs we developed potent antinociceptive agents, typified by CMI-936 and CMI-1145, whose antinociception, unlike that of epibatidine, is mediated via muscarinic receptors. Subsequently, we used specific muscarinic toxins and antagonists to delineate the muscarinic receptor subtype involved in the antinociception evoked by these agents. Thus, the antinociception produced by CMI-936 and CMI-1145 is inhibited substantially by 1) intrathecal injection of the specific muscarinic M4 toxin, muscarinic toxin-3; 2) intrathecally administered pertussis toxin, which inhibits the G proteins coupled to M2 and M4 receptors; and 3) s.c. injection of the M2/M4 muscarinic antagonist himbacine. These results demonstrate that the antinociception elicited by these epibatidine analogs is mediated via muscarinic M4 receptors located in the spinal cord. Compounds that specifically target the M4 receptor therefore may be of substantial value as alternative analgesics to the opiates. The American Society for Pharmacology and Experimental Therapeutics