Chain-lengthened and imidazoline analogues of nicotine

Analogues of nicotine (1) and azanicotine (3) were prepared with an additional methylene group inserted between the two rings (i.e., homonicotine and homoazanicotine; 6 and 5, respectively). Although 6 (Ki=3110 nM) and 3 (Ki=206 nM) bind at nACh receptors with ≥100-fold lower affinity than nicotine (Ki=2.1 nM), 5 displays high affinity (Ki=7.8 nM). Like nicotine (ED50=12 μg/mouse), both 3 and 5 (ED50=21 and 19 μg/mouse, respectively) produced antinociceptive activity in the tail-flick assay following intrathecal administration. The antinociceptive actions of 3 and 5, unlike those of nicotine, were not antagonized by mecamylamine. Compounds 3 and 5 might represent novel analgesic agents that act via a non-nicotinic mechanism, or via a nicotinic mechanism that is distinct from that mediating the antinociceptive actions of nicotine.