Abstract

Because mecamylamine, a nicotinic receptor antagonist, is used so often in nicotine research and because mecamylamine may have important therapeutic properties clinically, it is important to fully explore and understand its pharmacology. In the present study, the efficacy and potency of mecamylamine and its stereoisomers were evaluated as inhibitors of human α3β4, α3β2, α7, and α4β2 nicotinic acetylcholine receptors (nAChRs), as well as mouse adult type muscle nAChRs and rat N-methyl-d-aspartate (NMDA) receptors expressed in Xenopus oocytes. The selectivity of mecamylamine for neuronal nAChR was manifested primarily in terms of slow recovery rates from mecamylamine-induced inhibition. Neuronal receptors showed a prolonged inhibition after exposure to low micromolar concentrations of mecamylamine. Muscle-type receptors showed a transient inhibition by similar concentrations of mecamylamine, and NMDA receptors were only transiently inhibited by higher micromolar concentrations. Mecamylamine inhibition of neuronal nAChR was noncompetitive and voltage dependent. Although there was little difference between S-(+)-mecamylamine andR-(−)-mecamylamine in terms of 50% inhibition concentration values for a given receptor subtype, there appeared to be significant differences in the off-rates for the mecamylamine isomers from the receptors. Specifically, S-(+)-mecamylamine appeared to dissociate more slowly from α4β2 and α3β4 receptors than did R-(−)-mecamylamine. In addition, it was found that muscle-type receptors appeared to be somewhat more sensitive toR-(−)-mecamylamine than toS-(+)-mecamylamine. Together, these findings suggest that in chronic (i.e., therapeutic) application,S-(+)-mecamylamine might be preferable toR-(−)-mecamylamine in terms of equilibrium inactivation of neuronal receptors with decreased side effects associated with muscle-type receptors.