Abstract
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 α4β2* and α7* 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 α4β2* 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 KB 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.
Footnotes
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↵1 Current address: Targacept, Inc., 200 East First St., Suite 300, Winston-Salem, NC 27101-4165.
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↵2 Current address: AstraZeneca, 1800 Concord Pike, P. O. Box 15437, Wilmington, DE 19850-5437.
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This research was supported by National Institutes of Health Grants DA00399 and DA10934.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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DOI: 10.1124/jpet.103.051789.
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ABBREVIATIONS: nAChR, neuronal nicotinic acetylcholine receptor; MLA, methyllycaconitine; DA, dopamine; NONI, N-n-octylnicotinium iodide; NDNI, N-n-decylnicotinium iodide; NMPI, N-methylpyridinium iodide; NEPI, N-ethylpyridinium iodide; NPrPI, N-n-propylpyridinium iodide; NBuPI, N-n-butylpyridinium iodide; NPPI, N-n-pentylpyridinium iodide; NHxPI, N-n-hexylpyridinium iodide; NHPI, N-n-heptylpyridinium iodide; NOPI, N-n-octylpyridinium iodide; NNPI, N-n-nonylpyridinium iodide; NDPI, N-n-decylpyridinium iodide; NUPI, N-n-undecylpyridinium iodide; NDDPI, N-n-dodecylpyridinium iodide; NPDPB, N-n-pentadecylpyridinium bromide; NEcPB, N-n-eicosylpyridinium bromide; ANOVA, analysis of variance.
- Received March 17, 2003.
- Accepted May 16, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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