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NEUROPHARMACOLOGY

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

Preclinical Research, Targacept, Inc., Winston-Salem, North Carolina

(±)-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 4β2 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 4β2 NNRs. In addition, we demonstrated that TC-5214 potentiated and TC-5213 inhibited agonist-induced activation of HS 4β2 NNRs. The stereoselectivity of mecamylamine enantiomers at HS and LS 4β2 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.

Address correspondence to: Dr. Patrick M. Lippiello, Targacept, Inc., 200 East 1st Street, Suite 300, Winston-Salem, NC 27101. E-mail: lippiello{at}targacept.com