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 [ 3 H]nicotine binding sites ( K i =330 nM), but did not inhibit [ 3 H]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 86 Rb + 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 [ 3 H]methyllycaconitine binding sites ( K i =1.61 μM), but did not inhibit [ 3 H]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.