Bis-Azaaromatic quaternary ammonium analogues: ligands for α4β2* and α7* subtypes of neuronal nicotinic receptors

Abstract

A series of bis-nicotinium, bis-pyridinium, bis-picolinium, bis-quinolinium and bis-isoquinolinium compounds was evaluated for their binding affinity at nicotinic acetylcholine receptors (nAChRs) using rat brain membranes. N, N′-Decane-1,12-diyl-bis-nicotinium diiodide (bNDI) exhibited the highest affinity for [ 3H]nicotine binding sites ( K i=330 nM), but did not inhibit [ 3H]methyllycaconitine binding ( K i >100 μM), indicative of an interaction with α4β2*, but not α7* receptor subtypes, respectively. Also, bNDI inhibited (IC 50=3.76 μM) nicotine-evoked 86Rb + efflux from rat thalamic synaptosomes, indicating antagonist activity at α4β2* nAChRs. N, N′-Dodecane-1,12-diyl-bis-quinolinium dibromide (bQDDB) exhibited highest affinity for [ 3H]methyllycaconitine binding sites ( K i=1.61 μM), but did not inhibit [ 3H]nicotine binding ( K i>100 μM), demonstrating an interaction with α7*, but not α4β2* nAChRs. Thus, variation of N- n-alkyl chain length together with structural modification of the azaaromatic quaternary ammonium moiety afforded selective antagonists for the α4β2* nAChR subtype, as well as ligands with selectivity at α7* nAChRs.