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

摘要

Structural simplification of N-n-alkylnicotinium analogs, antagonists at neuronal nicotinic acetylcholine receptors (nAChRs), was achieved by removal of the N-methylpyrrolidion moiety affording N-n-alkylpyridinium analogs with carbon chain lengths of C1 to C20. N-n-Alkylpyridinium analog inhibitio of [~3H] nicotine and [~3H] methyllycaconitine binding to rat brain membranes assessed interaction with alpha 4 beta2* and alpha 7* nAChRs, respectively, whereas ihhibition of nicotine-evoked ~3H overflow from [~3H]dopamine ([~3H]DA)-preloaded rat triatal slices assessed antagonist action at nAChR subtypes mediating nicotine-evoked DA release. No inhibition of [~3H]methyllycaconitine binding was observed, although N-n-alkylpyridinium analogs had low affinity for [~3H] nicotine binding sites, i.e., 1 to 3 orders of magnitude lower than that of the respective N-n-alkylnico-tinium analogs. These results indicate that the N-methylpyrrolidino moiety in the N-n-alkylnicotinium analogs is a structural requirement for potent inhibition of alpha 4 beta 2* nAChRs. Inportantly N-n-alkylpyridinium analogs with n-alkyl chains