ANTINOCICEPTIVE PROFILE OF 3-ALPHA-TROPANYL-(2-CL)-ACID PHENOXYBUTYRATE (SM-21) - A NOVEL ANALGESIC WITH A PRESYNAPTIC CHOLINERGIC MECHANISM OF ACTION

The antinociceptive effect of (+/-)-3-alpha-tropanyl-(2-Cl)-acid pheno xybutyrate (SM-21) (10-40 mg kg(-1) s.c., 10-30 mg kg(-1) i.p., 20-60 mg kg(-1) p.o., 3-20 mg kg(-1) i.v. and 5-20 mu g per mouse i.c.v.) wa s examined in rodents and guinea pigs by using the hot-plate, abdomina l constriction, tail-flick and paw-pressure tests. The antinociception produced by (+/-)-SM-21 was prevented by atropine, pirenzepine and he micholinium-3 but not by quinpirole, R-(alpha)-methylhistamine, l]meth yl-5-floro-2-methoxy-1H-indole-3-carboxylate hydrochloride, N-6-cyclop entyladenosine, ethoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine hyd robromide, naloxone, 3-aminopropyl-diethoxy-methyl-phosphinic acid or reserpine. On the basis of the above data, it can be postulated that(/-)-SM-21 exerted an antinociceptive effect mediated by a central pote ntiation of cholinergic transmission. Affinity profiles of(+/-)-SM-21 for muscarinic receptor subtypes, determined by functional studies (ra bbit vas deferens for M-1, guinea pig atrium for M-2, guinea pig ileum for M-3 and immature guinea pig uterus for putative M-4) have shown a selectivity ratio M-2/M-1 of 4.6 that, although very low, might be re sponsible for the antinociception induced by (+)-SM-21 through an incr ease in ACh extracellular levels. In the antinociceptive dose range, ( +/-)-SM-21 did not impair mouse performance evaluated by the rota-rod and hole-board tests.