Synthesis and biological evaluation at nicotinic acetylcholine receptors of N-arylalkyl- and N-aryl-7-azabicyclo[2.2.1]heptanes.

A new series of N-arylalkyl-substituted 7-azabicyclo[2.2.1]heptanes and N-aryl-substituted 7-azabicyclo[2.2.1]heptanes were synthesized and evaluated as potential ligands for neuronal nicotinic acetylcholine receptors. The in vitro binding affinities (K(i)) of the 7-azabicyclo[2.2.1]heptane derivatives were measured by inhibition of [(3)H]cytisine binding to rat brain tissue. The most potent ligand of the series was found to be N-(3-pyridylmethyl)-7-azabicyclo[2.2.1]heptane (5b, K(i) = 98 nM). The chloro analogue (5a, K(i) = 245 nM) 5a and epibatidine (1) produced dose-dependent analgesia in both hotplate and tail-flick tests when administered subcutaneously. However, when compounds 1 and 5a,b were administered intrathecally, all produced analgesia in the tail-flick test but only 5a produced analgesia in the hotplate test.