Received for publication October 2, 2008.
Revised October 27, 2008.
Accepted for publication October 27, 2008.

DIFFERENTIAL PHARMACOLOGIES OF MECAMYLAMINE ENANTIOMERS: POSITIVE ALLOSTERIC MODULATION AND NON-COMPETITIVE INHIBITION

Abstract

(±) Mecamylamine is a racemic mixture of a widely used brain-permeant non-competitive 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-(HS) and low-sensitivity (LS) isoforms of the human (42) NNR subtype expressed in SH-EP1 cells. We found that at low concentrations (µM range) S-(+)-mecamylamine (TC-5214) was more effective than R-(-)-mecamylamine (TC-5213) in inhibiting the LS 42 NNRs. In addition we demonstrated that TC-5214 potentiated, and TC-5213 inhibited agonist-induced activation of HS 42 NNRs. The stereoselectivity of mecamylamine enantiomers at HS and LS 42 receptors demonstrates that TC-5214 is the preferred stereoisomer for selective activation of HS, while 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.

Key words: acetylcholine, cholinergic, electrophysiology, mecamylamine, nicotinic, receptors