N-n-alkylnicotinium analogs, a novel class of nicotinic receptor antagonists: Interaction with α4β2* and α7* Neuronal nicotinic receptors

The current study demonstrates that N-n-alkylnicotinium analogs with increasing n-alkyl chain lengths from 1 to 12 carbons have varying affinity (K_i = 90 nM-20 μM) for S-(-)-[³H]nicotine binding sites in rat striatal membranes. A linear relationship was observed such that increasing n-alkyl chain length provided increased affinity for the α4β2* nicotinic acetylcholine receptor (nAChR) subtype, with the exception of N-n-octylnicotinium iodide (NONI). The most potent analog was N-n-decylnicotinium iodide (NDNI; K_i = 90 nM). In contrast, none of the analogs in this series exhibited high affinity for the [³H]methyllycaconitine binding site, thus indicating low affinity for the α7* nAChR. The C₈ analog, NONI, had low affinity for S-(-)-[³H]nicotine binding sites but was a potent inhibitor of S-(-)-nicotine-evoked [³H]dopamine (DA) overflow from superfused striatal slices (IC₅₀ = 0.62 μM), thereby demonstrating selectivity for the nAChR subtype mediating S-(-)-nicotine-evoked [³H]DA overflow (α3α6β2* nAChRs). Importantly, the N-n-alkylnicotinium analog with highest affinity for the α4β2* subtype, NDNI, lacked the ability to inhibit S-(-)-nicotine-evoked [³H]DA overflow and, thus, appears to be selective for α4β2* nAChRs. Furthermore, the present study demonstrates that the interaction of these analogs with the α4β2* subtype is via a competitive mechanism. Thus, selectivity for the α4β2* subtype combined with competitive interaction with the S-(-)-nicotine binding site indicates that NDNI is an excellent candidate for studying the structural topography of α4β2* agonist recognition binding sites, for identifying the antagonist pharmacophore on the α4β2* nAChR, and for defining the role of this subtype in physiological function and pathological disease states.