New Rigid Nicotine Analogues, Carrying a Norbornane Moiety, Are Potent Agonists of alpha 7 and alpha 3*Nicotinic Receptors

A three-dimensional database search has been applied to design a series of endo- and exo-3-(pyridin-3-yl)bicyclo[2.2.1]heptan-2-amines as nicotinic receptor ligands. The synthesized compounds were tested in radioligand binding assay on rat cortex against [H-3]-cytisine and [3H]-methyllycaconitine to measure their affinity for alpha 4 beta 2* and alpha 7* nicotinic receptors. The new derivatives showed some preference for the alpha 4 beta 2* over the alpha 7* subtype, with their affinity being dependent on the endo/exo isomerism and on the methylation degree of the basic nitrogen. The endo primary amines displayed the lowest K-i values on both receptor subtypes. Selected compounds (1a, 2a, 3a, and 6a) were tested on heterologously expressed alpha 4 beta 2, alpha 7, and alpha 3 beta 2 receptors and on SHSY-5Y cells. Compounds 1a and 2a showed alpha 4 beta 2 antagonistic properties while behaved as full agonists on recombinant alpha 7 and on SHSYSY cells. On the alpha 3 beta 2 subtype, only the chloro derivative 2a showed full agonist activity and submicromolar potency (EC50 = 0.43 mu M). The primary amines described here represent new chemotypes for the alpha 7 and alpha 3* receptor subtypes.