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

PAOLA V. PLAZAS; JESSICA SAVINO; SEBASTIAN KRACUN; MARIA E GOMEZ CASATI; ELEONORA KATZ; CHRISTOPHER G. PARSONS; NEIL S. MILLAR; A. BELÉN ELGOYHEN

San Diego, California, USA

Congreso; Society for Neuroscience 37th Annual Meeting, Satellite on “Nicotinic Acetylcholine Receptors as Therapeutics Targets”, San Diego, USA; 2007

Nicotinic cholinergic receptors are affected by a variety of non-cholinergic drugs with biological and/or clinical relevance at concentrations at which they act on their classical targets. In particular, the adamantane derivative 3,5-dimethyl-1- adamantanamine (memantine) is a well-established blocker of ligand-gated ion channels permeable to Ca2+ such as the NMDA type glutamate receptor and is currently used in therapeutics for the treatment of Alzheimer´s disease. Neramexane, a novel amino-alkyl-cyclohexane derivative, is also a non-competitive NMDA receptor antagonist, and is presently in phase II clinical trials for various indications including Alzheimer´s disease, chronic pain and tinnitus. In the present work, we have analyzed the effects of neramexane on recombinant rat a9a10 nicotinic acetylcholine receptors expressed in Xenopus laevis oocytes. We compared its effects with those of memantine, a well-studied pore blocker of NMDA receptors. 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 therapeutic areas that involve inner ear pathologies.