N-n-alkylnicotinium analogs, a novel class of nicotinic receptor antagonist: Inhibition of S(-)-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.