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Research ArticleNEUROPHARMACOLOGY

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

Vladimir P. Grinevich, Peter A. Crooks, Sangeetha P. Sumithran, Aaron J. Haubner, Joshua T. Ayers and Linda P. Dwoskin
Journal of Pharmacology and Experimental Therapeutics September 2003, 306 (3) 1011-1020; DOI: https://doi.org/10.1124/jpet.103.051789
Vladimir P. Grinevich
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Peter A. Crooks
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Sangeetha P. Sumithran
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Aaron J. Haubner
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Joshua T. Ayers
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Linda P. Dwoskin
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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

  • ↵1 Current address: Targacept, Inc., 200 East First St., Suite 300, Winston-Salem, NC 27101-4165.

  • ↵2 Current address: AstraZeneca, 1800 Concord Pike, P. O. Box 15437, Wilmington, DE 19850-5437.

  • This research was supported by National Institutes of Health Grants DA00399 and DA10934.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • DOI: 10.1124/jpet.103.051789.

  • 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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Journal of Pharmacology and Experimental Therapeutics: 306 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 306, Issue 3
1 Sep 2003
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Research ArticleNEUROPHARMACOLOGY

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

Vladimir P. Grinevich, Peter A. Crooks, Sangeetha P. Sumithran, Aaron J. Haubner, Joshua T. Ayers and Linda P. Dwoskin
Journal of Pharmacology and Experimental Therapeutics September 1, 2003, 306 (3) 1011-1020; DOI: https://doi.org/10.1124/jpet.103.051789

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Research ArticleNEUROPHARMACOLOGY

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

Vladimir P. Grinevich, Peter A. Crooks, Sangeetha P. Sumithran, Aaron J. Haubner, Joshua T. Ayers and Linda P. Dwoskin
Journal of Pharmacology and Experimental Therapeutics September 1, 2003, 306 (3) 1011-1020; DOI: https://doi.org/10.1124/jpet.103.051789
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