Chain-lengthened and imidazoline analogues of nicotine

Analogues of nicotine (1) and azanicotine (3) were prepared with an additio nal methylene group inserted between the two rings (i.e., homonicotine and homoazanicotine; 6 and 5, respectively). Although 6 (K-i = 3110 nM) and 3 ( K-i = 206 nM) bind at nACh receptors with greater than or equal to 100-fold lower affinity than nicotine (K-i=2.1nM), 5 displays high affinity (K-i=7. 8nM). Like nicotine (ED50=12 mug/mouse), both 3 and 5 (ED50=21 and 19 mug/m ouse, respectively) produced antinociceptive activity in the tail-flick ass ay following intrathecal administration. The antinociceptive actions of 3 a nd 5, unlike those of nicotine, were not antagonized by mecamylamine. Compo unds 3 and 5 might represent novel analgesic agents that act via a non-nico tinic mechanism, or via a nicotinic mechanism that is distinct from that me diating the antinociceptive actions of nicotine. (C) 2000 Elsevier Science Ltd. All rights reserved.