It is believed that nicotine exerts its psychoactive and addictive effects through neuronal nicotinic receptors (nAChRs). Surprisingly, few systematic structure-activity relationship (SAR) studies have been undertaken with nicotine. The major goal of our laboratory is to characterize the mechanisms by which nicotine produces some of its behavioral effects, with the ultimate aim of developing novel nicotine receptor ligands. Nicotine analogs with a wide range of receptor affinities were synthesized and evaluated for their ability to reduce spontaneous activity, produce antinociception, and engender nicotine-like responding in drug discrimination. Mecamylamine antagonism was then used to verify that these effects were mediated through the nicotinic receptor. Our results showed that an intact pyrrolidine ring, although not essential, appears to be optimal for nicotine activity and that bulky substituents dramatically attenuate receptor affinity. In addition, the "pyrrolidine" N in the up position i s more important for activity than the down position. Epibatidine analogs revealed that halogen substitution at position 2 was not sufficient to account for all of epibatidine's potency. Finally, correlation of receptor affinity with pharmacological potency suggested that nicotine-induced antinociception and hypomotility may involve the activation of nicotinic receptors containing an a4p2 subunit combination. These results clearly show that this strategy can be used to distinguish among nicotine analogs with different mechanisms of action and can serve as the basis for an evaluation model. Drug Dev. Res. 38:177-187 0 19% Wiley-Liss, Inc.