Vol. 301, Issue 3, 1088-1096, June 2002

N-n-Alkylnicotinium Analogs, A Novel Class of Nicotinic Receptor Antagonist: Inhibition of S()-Nicotine-Evoked [³H]Dopamine Overflow from Superfused Rat Striatal Slices

Lincoln H. Wilkins, Jr., Aaron Haubner, Joshua T. Ayers, Peter A. Crooks and Linda P. Dwoskin

College of Pharmacy, University of Kentucky, Lexington, Kentucky

The structure of the S()-nicotine molecule was modified via N-n-alkylation of the pyridine-N atom to afford a series of N-n-alkylnicotinium iodide salts with carbon chain lengths varying between C₁ and C₁₂. The ability of these analogs to evoke [³H] overflow and inhibit S()-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, and N-n-dodecylnicotinium iodide (NDDNI; C₁₂) at 10 µM, whereas N-n-octylnicotinium iodide (NONI; C₈), N-n-heptylnicotinium iodide (NHpNI; C₇), and N-n-hexylnicotinium iodide (C₆) evoked [³H] overflow at 100 µM. Thus, intrinsic activity at these concentrations prohibited assessment of inhibitory activity. The most potent N-n-alkylnicotinium analog to inhibit S()-nicotine-evoked [³H] overflow was NDDNI, with an IC₅₀ value of 9 nM. NHpNI, NONI, and N-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--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 of S()-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 (K_i value = 80.2 nM). Thus, modification of the S()-nicotine molecule converts this agonist into an antagonist at nAChRs, mediating S()-nicotine-evoked DA release in striatum.