Inhibition of the α9α10 nicotinic cholinergic receptor by neramexane, open channel blocker of N-methyl-D-aspartatc an receptors

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 alpha 9 alpha 10 nicotinic acetylcholine receptors expressed in Xenopus 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 acetylcboline-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 mu M. Finally, clinically-relevant concentrations of neramexane blocked native alpha 9 alpha O-containing nicotinic acetylcholine receptors ofrat inner hair cells, thus demonstrating a possible in vivo relevance in potentially unexplored therapeutic areas. (c) 2007 Elsevier B.V. All rights reserved.