%0 Journal Article %A Lincoln H. Wilkins, Jr. %A Aaron Haubner %A Joshua T. Ayers %A Peter A. Crooks %A Linda P. Dwoskin %T N-n-Alkylnicotinium Analogs, A Novel Class of Nicotinic Receptor Antagonist: Inhibition ofS(−)-Nicotine-Evoked [3H]Dopamine Overflow from Superfused Rat Striatal Slices %D 2002 %R 10.1124/jpet.301.3.1088 %J Journal of Pharmacology and Experimental Therapeutics %P 1088-1096 %V 301 %N 3 %X The structure of the S(−)-nicotine molecule was modified via N-n-alkylation of the pyridine-N atom to afford a series ofN-n-alkylnicotinium iodide salts with carbon chain lengths varying between C1 and C12. The ability of these analogs to evoke [3H] overflow and inhibitS(−)-nicotine-evoked [3H] overflow from [3H]dopamine ([3H]DA)-preloaded rat striatal slices was determined. At high concentrations, analogs with chain lengths ≥C6 evoked [3H] overflow. Specifically, N-n-decylnicotinium iodide (NDNI; C10) evoked significant [3H] overflow at 1 μM, andN-n-dodecylnicotinium iodide (NDDNI; C12) at 10 μM, whereasN-n-octylnicotinium iodide (NONI; C8), N-n-heptylnicotinium iodide (NHpNI; C7), andN-n-hexylnicotinium iodide (C6) evoked [3H] overflow at 100 μM. Thus, intrinsic activity at these concentrations prohibited assessment of inhibitory activity. The most potentN-n-alkylnicotinium analog to inhibitS(−)-nicotine-evoked [3H] overflow was NDDNI, with an IC50 value of 9 nM. NHpNI, NONI, andN-n-nonylnicotinium iodide (C9) also inhibited S(−)-nicotine-evoked [3H] overflow with IC50 values of 0.80, 0.62, and 0.21 μM, respectively. In comparison, the competitive neuronal nicotinic acetylcholine receptor (nAChR) antagonist, dihydro-β-erythroidine, had an IC50 of 1.6 μM. A significant correlation of N-n-alkyl chain length with analog-induced inhibition was observed, with the exception of NDNI, which was devoid of inhibitory activity. The mechanism of N-n-alkylnicotinium-induced inhibition of the high-affinity, low-capacity component ofS(−)-nicotine-evoked [3H] overflow was determined via Schild analysis, using the representative analog, NONI. Linear Schild regression and slope not different from unity suggested that NONI competitively interacts with a single nAChR subtype to inhibit S(−)-nicotine-evoked [3H]DA release (Ki value = 80.2 nM). Thus, modification of the S(−)-nicotine molecule converts this agonist into an antagonist at nAChRs, mediatingS(−)-nicotine-evoked DA release in striatum. The American Society for Pharmacology and Experimental Therapeutics %U https://jpet.aspetjournals.org/content/jpet/301/3/1088.full.pdf