Jl. Ellis et al., Development of muscarinic analgesics derived from epibatidine: Role of theM-4 receptor subtype, J PHARM EXP, 288(3), 1999, pp. 1143-1150
Citations number
36
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
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.