Inhibition of the alpha9 alpha10 nicotinic acetylcholine receptor by neramexane, an open channel blocker of N-methyl-D-aspartate receptors

PLAZAS PV; SAVINO J; KRACUN S; GOMEZ CASATI ME; KATZ E; PARSONS CG; MILLAR NS; ELGOYHEN AB

EUROPEAN JOURNAL OF PHARMACOLOGY

Año: 2007 vol. 566 p. 11 - 19

0014-2999

In this study we report the effects of neramexane, a novel amino-alkyl-cyclohexane derivative that is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, on recombinant rat a9a10 nicotinic acetylcholine receptors expressed in Xenopuslaevis oocytes. We compared its effects with those of memantine, a well-studied pore blocker of NMDA receptors, currently used in therapeutics for the treatment of Alzheimer´s disease. Our results indicate that both compounds block acetylcholine-evoked responses at micromolar concentrations with a rank order of potency of neramexane > memantine, P < 0.05. Block by neramexane of acetylcholine responses was not overcome at high concentrations of the agonist, indicative of a non-competitive inhibition. The lack of interaction of neramexane with the ligand binding domain was confirmed by radioligand binding experiments in transfected tsA201 cells. Moreover, block did not involve an increase in desensitization kinetics, it was independent of the resting potential of the membrane at low concentrations of neramexane and slightly voltage-dependent at concentrations higher than 1 mM. Finally, clinically-relevant concentrations of neramexane blocked native a9a10-containing nicotinic acetylcholine receptors of rat inner hair cells, thus demonstrating a possible in vivo relevance in potentially unexplored therapeutic areas