Development of muscarinic analgesics derived from epibatidine: Role of theM-4 receptor subtype

Epibatidine, a neurotoxin isolated from the skin of Epipedobates tricolor, is an efficacious antinociceptive agent with a potency 200 times that of mo rphine. The toxicity of epibatidine, because of its nonspecificity for both peripheral and central nicotinic receptors, precludes its development as a n analgesic. During the synthesis of epibatidine analogs we developed poten t antinociceptive agents, typified by CMI-936 and CMI-1145, whose antinocic eption, unlike that of epibatidine, is mediated via muscarinic receptors. S ubsequently, we used specific muscarinic toxins and antagonists to delineat e the muscarinic receptor subtype involved in the antinociception evoked by these agents. Thus, the antinociception produced by CMI-936 and CMI-1145 i s inhibited substantially by I)intrathecal injection of the specific muscar inic M-4, toxin, muscarinic toxin-3; 2) intrathecally administered pertussi s toxin, which inhibits the G proteins coupled to M-2 and M-4 receptors; an d 3) s.c. injection of the M-2/M-4, muscarinic antagonist himbacine. These results demonstrate that the antinociception elicited by these epibatidine analogs is mediated via muscarinic M-4 receptors located in the spinal cord . Compounds that specifically target the M-4 receptor therefore may be of s ubstantial Value as alternative analgesics to the opiates.