Inhibition of the a9a10 nicotinic cholinergic 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

San Diego, USA

Simposio; Satellite Meeting of the 37th Annual Meeting, Society for Neuroscience: Nicotinic Acetycholine Receptors as Therapeutic Targets; 2007

In this study we report the effects of neramexane, a novel amino-alkyl-cyclohexane derivative that is an uncompetitive NMDA receptor antagonist, on recombinant rat a9a10 nAChRs expressed in X. laevis 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 ACh-evoked responses at micromolar concentrations with a rank order of potency of neramexane > memantine, p < 0.05. Block by neramexane of ACh responses was not overcome at high concentrations of the agonist, indicative of a noncompetitive 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 nAChRs of rat inner hair cells, thus demonstrating a possible in vivo relevance in potentially unexplored therapeutic areas.