N-n-Alkylpyridinium Analogs, a Novel Class of Nicotinic Receptor Antagonists: Selective Inhibition of Nicotine-Evoked [3H]Dopamine Overflow from Superfused Rat Striatal Slices

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-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 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.