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NEUROPHARMACOLOGY

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

College of Pharmacy, University of Kentucky, Lexington, Kentucky

Structural simplification of N-n-alkylnicotinium analogs, antagonists at neuronal nicotinic acetylcholine receptors (nAChRs), was achieved by removal of the N-methylpyrrolidino moiety affording N-n-alkylpyridinium analogs with carbon chain lengths of C1 to C20. N-n-Alkylpyridinium analog inhibition of [³H]nicotine and [³H]methyllycaconitine binding to rat brain membranes assessed interaction with 42^* and 7^* nAChRs, respectively, whereas inhibition of nicotine-evoked ³H overflow from [³H]dopamine ([³H]DA)-preloaded rat striatal 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-alkylnicotinium analogs. These results indicate that the N-methylpyrrolidino moiety in the N-n-alkylnicotinium analogs is a structural requirement for potent inhibition of 42^* nAChRs. Importantly, N-n-alkylpyridinium analogs with n-alkyl chains < C10 did not inhibit nicotine-evoked [³H]DA overflow, whereas analogs with n-alkyl chains ranging from C10 to C20 potently and completely inhibited nicotine-evoked [³H]DA overflow (IC₅₀ = 0.12-0.49 µM), with the exceptions of N-n-pentadecylpyridinium bromide (C15) and N-n-eicosylpyridinium bromide (C20), which exhibited maximal inhibition of 50%. The mechanism of inhibition of a representative analog of this structural series, N-n-dodecylpyridinium iodide, was determined by Schild analysis. Linear Schild regression with slope not different from unity indicated competitive antagonism at nAChRs mediating nicotine-evoked [³H]DA overflow and a K_B value of 0.17 µM. Thus, the simplified N-n-alkylpyridinium analogs are potent, selective, and competitive antagonists of nAChRs mediating nicotine-evoked [³H]DA overflow, indicating that the N-methylpyrrolidino moiety is not a structural requirement for interaction with nAChR subtypes mediating nicotine-evoked DA release.

Address correspondence to: Dr. Linda P. Dwoskin, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082. E-mail: ldwoskin{at}uky.edu

This article has been cited by other articles:

				L. P. Dwoskin, T. E. Wooters, S. P. Sumithran, K. B. Siripurapu, B. M. Joyce, P. R. Lockman, V. K. Manda, J. T. Ayers, Z. Zhang, A. G. Deaciuc, et al. N,N'-Alkane-diyl-bis-3-picoliniums as Nicotinic Receptor Antagonists: Inhibition of Nicotine-Evoked Dopamine Release and Hyperactivity J. Pharmacol. Exp. Ther., August 1, 2008; 326(2): 563 - 576. [Abstract] [Full Text] [PDF]