PT  - JOURNAL ARTICLE
AU  - James L. Ellis
AU  - Dean Harman
AU  - Javier Gonzalez
AU  - Michael L. Spera
AU  - Ronggang Liu
AU  - T. Y. Shen
AU  - Donna M. Wypij
AU  - Fangming Zuo
TI  - Development of Muscarinic Analgesics Derived from Epibatidine: Role of the M<sub>4</sub> Receptor Subtype
DP  - 1999 Mar 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1143--1150
VI  - 288
IP  - 3
4099  - http://jpet.aspetjournals.org/content/288/3/1143.short
4100  - http://jpet.aspetjournals.org/content/288/3/1143.full
SO  - J Pharmacol Exp Ther1999 Mar 01; 288
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