Pharmacological effects of epibatidine optical enantiomers.

The pharmacology of synthetic D- and L-epibatidine, an alkaloid originally characterized from frog skin, were studied in different behavioral tests in mice and rats. The two enantiomers have potent antinociceptive activity in mice using the tail-flick test, with an ED50 of 6.1 and 6.6 micrograms/kg for L- and D-epibatidine respectively. Epibatidine enantiomers were 200 x more potent than L-nicotine as an antinociceptive agent in mice after s.c. administration. Their analgesic effect was blocked by mecamylamine but not naloxone, an opiate antagonist. Both D- and L-epibatidine have high affinity (Ki 54.7 and 55.0 pM, respectively) for [3H]nicotine binding site in rat brain. In addition, they reduced mice locomotor activity and body temperature in a dose-dependent manner. In rats trained with nicotine (0.4 mg/kg), epibatidine enantiomers engendered nicotine-like responding in a dose-related manner with an ED50 of 1.00 and 0.93 micrograms/kg for D and L, respectively. The discriminative effect of L- and D-epibatidine in rats was blocked by mecamylamine but not by hexamethonium. As in binding results, there was no significant enantioselectivity for these effects in our study.