Inhibition of the alpha9alpha10 nicotinic cholinergic receptor by neramexane, an open channel blocker of N-methyl-D-aspartate receptors¡¨

PAOLA V. PLAZAS; JESSICA SAVINO; SEBASTIÁN KRACUNE; MARIA E. GOMEZ-CASATI; ELEONORA KATZ; CHRISTOPHER G. PARSONS; NEIL S. MILLAR; ANA B ELGOYHEN

EUROPEAN JOURNAL OF PHARMACOLOGY

ELSEVIER SCIENCE BV

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 alpha9alpha10 nicotinic acetylcholine receptors expressed in Xenopus laevis oocytes. We compared itseffects with those of memantine, a well-studied pore blocker of NMDA receptors, currently used in therapeutics for the treatment of Alzheimer´sdisease. Our results indicate that both compounds block acetylcholine-evoked responses at micromolar concentrations with a rank order ofpotency of neramexane N memantine, Pb0.05. Block by neramexane of acetylcholine responses was not overcome at high concentrations of theagonist, indicative of a non-competitive inhibition. The lack of interaction of neramexane with the ligand binding domain was confirmed byradioligand binding experiments in transfected tsA201 cells. Moreover, block did not involve an increase in desensitization kinetics, it wasindependent of the resting potential of the membrane at low concentrations of neramexane and slightly voltage-dependent at concentrations higherthan 1 microM. Finally, clinically-relevant concentrations of neramexane blocked native alpha9alpha10-containing nicotinic acetylcholine receptors of ratinner hair cells, thus demonstrating a possible in vivo relevance in potentially unexplored therapeutic areas.