PHARMACOLOGY OF NOVEL NICOTINIC ANALOGS

It is believed that nicotine exerts its psychoactive and addictive eff ects through neuronal nicotinic receptors (nAChRs). Surprisingly, few systematic structure-activity relationship (SAR) studies have been und ertaken with nicotine. The major goal of our laboratory is to characte rize the mechanisms by which nicotine produces some of its behavioral effects, with the ultimate aim of developing novel nicotine receptor l igands. Nicotine analogs with a wide range of receptor affinities were synthesized and evaluated for their ability to reduce spontaneous act ivity, produce antinociception, and engender nicotine-like responding in drug discrimination. Mecamylamine antagonism was then used to verif y that these effects were mediated through the nicotinic receptor. Our results showed that an intact pyrrolidine ring, although not essentia l, appears to be optimal for nicotine activity and that bulky substitu ents dramatically attenuate receptor affinity. In addition, the ''pyrr olidine'' N in the up position is 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 pharmacologica l potency suggested that nicotine-induced antinociception and hypomoti lity may involve the activation of nicotinic receptors containing an a lpha(2) beta(2) subunit combination. These results clearly show that t his strategy can be used to distinguish among nicotine analogs with di fferent mechanisms of action and can serve as the basis for an evaluat ion model. (C) 1996 Wiley-Liss, Inc.