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 (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 (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 (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.