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-quinoliniurn 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 (bND1) exhibited the highest affinity for [H-3]nicotine binding sites (K-i = 330 nM), but did not inhibit [H-3]methyllycaconitine binding (K-i > 100 muM), indicative of an interaction with alpha4beta2*, but not alpha7* receptor subtypes, respectively. Also, bND1 inhibited (IC50 = 3.76 muM) nicotine-evoked Rb-86(+) efflux from rat thalamic synaptosomes, indicating antagonist activity at alpha4beta2* nAChRs. N,N'-Dodecane-1,12-diyl-bis-quinolinium dibromide (bQDDB) exhibited highest affinity for [H-3]methyllycaconitine binding sites (K-i = 1.61 muM), but did not inhibit [H-3]nicotine binding (K-i > 100 muM), demonstrating an interaction with alpha7*, but not alpha4beta2* nAChRs. Thus, variation of N-n-alkyl chain length together with structural modification of the azaaromatic quaternary ammonium moiety afforded selective antagonists for the alpha4beta2* nAChR subtype, as well as ligands with selectivity at a7* nAChRs. (C) 2002 Elsevier Science Ltd. All rights reserved.