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Research ArticleNEUROPHARMACOLOGY

Differential Pharmacologies of Mecamylamine Enantiomers: Positive Allosteric Modulation and Noncompetitive Inhibition

Nikolai B. Fedorov, Lisa C. Benson, John Graef, Patrick M. Lippiello and Merouane Bencherif
Journal of Pharmacology and Experimental Therapeutics February 2009, 328 (2) 525-532; DOI: https://doi.org/10.1124/jpet.108.146910
Nikolai B. Fedorov
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Lisa C. Benson
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John Graef
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Patrick M. Lippiello
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Merouane Bencherif
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Abstract

(±)-Mecamylamine is a racemic mixture of a widely used brain-permeant noncompetitive inhibitor of muscle-type and neuronal nicotinic receptors (NNRs). The present studies evaluated whether the stereoisomers of this drug show different profiles for inhibition of the high-sensitivity (HS) and low-sensitivity (LS) isoforms of the human α4β2 NNR subtype expressed in subclonal human epithelial 1 cells. We found that at low concentrations (micromolar range), TC-5214 [S-(+)-mecamylamine] was more effective than TC-5213 [R-(-)-mecamylamine] in inhibiting the LS α4β2 NNRs. In addition, we demonstrated that TC-5214 potentiated and TC-5213 inhibited agonist-induced activation of HS α4β2 NNRs. The stereoselectivity of mecamylamine enantiomers at HS and LS α4β2 receptors demonstrates that TC-5214 is the preferred stereoisomer for selective activation of HS, whereas it is more effective in suppressing LS receptor function. This feature could be relevant to therapeutic applications where such a selective mechanism of action is required.

Footnotes

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

  • doi:10.1124/jpet.108.146910.

  • ABBREVIATIONS: NNR, neuronal nicotinic receptor; HS, high sensitivity; LS, low sensitivity; SH-EP1, subclonal human epithelial; ACh, acetylcholine; HEK, human embryonic kidney; TC-5214, S-(+)-mecamylamine; TC-5213, R-(-)-mecamylamine; ANOVA, analysis of variance; NE, norepinephrine; Nic, nicotine.

    • Received October 1, 2008.
    • Accepted October 27, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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Research ArticleNEUROPHARMACOLOGY

Differential Pharmacologies of Mecamylamine Enantiomers: Positive Allosteric Modulation and Noncompetitive Inhibition

Nikolai B. Fedorov, Lisa C. Benson, John Graef, Patrick M. Lippiello and Merouane Bencherif
Journal of Pharmacology and Experimental Therapeutics February 1, 2009, 328 (2) 525-532; DOI: https://doi.org/10.1124/jpet.108.146910

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Research ArticleNEUROPHARMACOLOGY

Differential Pharmacologies of Mecamylamine Enantiomers: Positive Allosteric Modulation and Noncompetitive Inhibition

Nikolai B. Fedorov, Lisa C. Benson, John Graef, Patrick M. Lippiello and Merouane Bencherif
Journal of Pharmacology and Experimental Therapeutics February 1, 2009, 328 (2) 525-532; DOI: https://doi.org/10.1124/jpet.108.146910
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