Pyrrolidine-modified and 6-substituted analogs of nicotine: a structure-affinity investigation

Article abstract of DOI:10.1016/S0223-5234(97)89850-9

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 presence is not an absolute requirement for activity, and 6-position substitution of the pyridine nucleus can influence both binding and functional activity. - Keywords: nicotine; nicotine receptor; drug discrimination; antinociception.