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

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 (Ki=330 nM), but did not inhibit [3H]methyllycaconitine binding (Ki>100 μM), indicative of an interaction with α4β2*, but not α7* receptor subtypes, respectively. Also, bNDI inhibited (IC50=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 (Ki=1.61 μM), but did not inhibit [3H]nicotine binding (Ki>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.