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
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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.108.146910.
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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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