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 muM) for S-(-)-[H-3] nicotine binding sites in rat striatal membranes. A linear relationship was observed such that increasing n-alkyl chain length provided increased affinity for the alpha4beta2* 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 [H-3] methyllycaconitine binding site, thus indicating low affinity for the alpha7* nAChR. The C-8 analog, NONI, had low affinity for S-(-)-[H-3] nicotine binding sites but was a potent inhibitor of S-(-)- nicotine-evoked [H-3] dopamine (DA) overflow from superfused striatal slices (IC50=0.62 muM), thereby demonstrating selectivity for the nAChR subtype mediating S-(-)-nicotine-evoked [H-3] DA overflow (alpha3alpha6beta2* nAChRs). Importantly, the N-n-alkylnicotinium analog with highest affinity for the alpha4beta2* subtype, NDNI, lacked the ability to inhibit S-(-)-nicotine-evoked [H-3] DA overflow and, thus, appears to be selective for alpha4beta2* nAChRs. Furthermore, the present study demonstrates that the interaction of these analogs with the alpha4beta2* subtype is via a competitive mechanism. Thus, selectivity for the alpha4beta2* subtype combined with competitive interaction with the S-(-)-nicotine binding site indicates that NDNI is an excellent candidate for studying the structural topography of alpha4beta2* agonist recognition binding sites, for identifying the antagonist pharmacophore on the alpha4beta2* nAChR, and for defining the role of this subtype in physiological function and pathological disease states.