Because the structural requirements for the binding of nicotine to central nicotine receptors remain largely uninvestigated, we undertook a systematic investigation of pyrrolidine ring-opened analogs. This led to a subsequent investigation of related conformationally restricted derivatives of these analogs. The results are reported relative to the binding of several well-known and widely used nicotine receptor ligands. Although none of the ring-opened analogs binds with higher affinity than (-)nicotine (K-i = 2.3 nM), 3-(N-methyl-N-ethylaminomethyl)pyridine (12a; K-i = 28 nM) binds with significant affinity. A conformationally restricted analog of 12a, N-methyl [2,7]naphthyridine 30b (K-i = 18 nM), binds with similar affinity. 6-Substitution of 12a and racemic nicotine seems to be tolerated when the substituent is halogen or methyl. In functional studies (hypolocomotion and antinociception in mice; stimulus generalization in nicotine-trained rats) 30b retains nicotine-like properties. Several of the 6-substituted compounds were 2 to 20 times more potent than (+/-)nicotine. Although the intact pyrrolidine ring of nicotine appears important for optimal affinity, its pre presence is not an absolute requirement for activity, and 6-position substitution of the pyridine nucleus can influence both binding and functional activity.
