Vol. 304, Issue 1, 400-410, January 2003

N-n-Alkylnicotinium Analogs, a Novel Class of Nicotinic Receptor Antagonists: Interaction with 42* and 7* Neuronal Nicotinic Receptors

Lincoln H. Wilkins, Jr., Vladimir P. Grinevich¹, Joshua T. Ayers², Peter A. Crooks and Linda P. Dwoskin

College of Pharmacy, University of Kentucky, Lexington, Kentucky

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 42* 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 7* 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 (362* nAChRs). Importantly, the N-n-alkylnicotinium analog with highest affinity for the 42* subtype, NDNI, lacked the ability to inhibit S-()-nicotine-evoked [³H]DA overflow and, thus, appears to be selective for 42* nAChRs. Furthermore, the present study demonstrates that the interaction of these analogs with the 42* subtype is via a competitive mechanism. Thus, selectivity for the 42* subtype combined with competitive interaction with the S-()-nicotine binding site indicates that NDNI is an excellent candidate for studying the structural topography of 42* agonist recognition binding sites, for identifying the antagonist pharmacophore on the 42* nAChR, and for defining the role of this subtype in physiological function and pathological disease states.