RT Journal Article SR Electronic T1 Differential Pharmacologies of Mecamylamine Enantiomers: Positive Allosteric Modulation and Noncompetitive Inhibition JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 525 OP 532 DO 10.1124/jpet.108.146910 VO 328 IS 2 A1 Nikolai B. Fedorov A1 Lisa C. Benson A1 John Graef A1 Patrick M. Lippiello A1 Merouane Bencherif YR 2009 UL http://jpet.aspetjournals.org/content/328/2/525.abstract AB (±)-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. The American Society for Pharmacology and Experimental Therapeutics