New Rigid Nicotine Analogues, Carrying a Norbornane Moiety, Are Potent Agonists of α7 and α3* 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 [3H]-cytisine and [3H]-methyllycaconitine to measure their affinity for α4β2*
and α7* nicotinic receptors. The new derivatives showed some
preference for the α4β2* over the α7* 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 Ki values on both
receptor subtypes. Selected compounds (1a, 2a, 3a, and 6a) were tested on heterologously
expressed α4β2, α7, and α3β2 receptors
and on SHSY-5Y cells. Compounds 1a and 2a showed α4β2 antagonistic properties while behaved as
full agonists on recombinant α7 and on SHSY5Y cells. On the
α3β2 subtype, only the chloro derivative 2a showed full agonist activity and submicromolar potency (EC50 = 0.43 μM). The primary amines described here represent new
chemotypes for the α7 and α3* receptor subtypes.