Vol. 282, Issue 1, 430-439, 1997

Antinociceptive Profile of 3--tropanyl-(2-Cl)-acid phenoxybutyrate (SM-21): A Novel Analgesic with a Presynaptic Cholinergic Mechanism of Action¹

Carla Ghelardini, Nicoletta Galeotti, Fulvio Gualtieri, Cristina Bellucci, Dina Manetti, Alberto Giotti , Petra Malmberg-Aiello, Alessandro Galli and Alessandro Bartolini

Department of Pharmacology (C.G., N.G., A.G., P.M.A., A.G., A.B.), University of Florence and Department of Pharmaceutical Sciences (F.G., C.B., D.M.), University of Florence, Florence, Italy

The antinociceptive effect of (±)-3--tropanyl-(2-Cl)-acid phenoxybutyrate (SM-21) (10-40 mg kg¹ s.c., 10-30 mg kg¹ i.p., 20-60 mg kg¹ p.o., 3-20 mg kg¹ i.v. and 5-20 µg per mouse i.c.v.) was examined in rodents and guinea pigs by using the hot-plate, abdominal constriction, tail-flick and paw-pressure tests. The antinociception produced by (±)-SM-21 was prevented by atropine, pirenzepine and hemicholinium-3 but not by quinpirole, R-()-methylhistamine, [1-[2(methylsufonyl)amino]ethyl]-4-piperidinyl]methyl-5-floro-2-methoxy-1H-indole-3-carboxylate hydrochloride, N⁶-cyclopentyladenosine, 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine hydrobromide, 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 potentiation of cholinergic transmission. Affinity profiles of (±)-SM-21 for muscarinic receptor subtypes, determined by functional studies (rabbit vas deferens for M₁, guinea pig atrium for M₂, guinea pig ileum for M₃ and immature guinea pig uterus for putative M₄) have shown a selectivity ratio M₂/M₁ of 4.6 that, although very low, might be responsible for the antinociception induced by (±)-SM-21 through an increase 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.