title: Inhibition of the alpha9alpha10 nicotinic cholinergic receptor by neramexane, an open channel blocker of N-methyl-D-aspartate receptors.
abstract: 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 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 microM. Finally, clinically-relevant concentrations of neramexane blocked native alpha9alpha10-containing nicotinic acetylcholine receptors of rat inner hair cells, thus demonstrating a possible in vivo relevance in potentially unexplored therapeutic areas.
authors.affiliation: Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina. plazas@dna.uba.ar
authors.forename: Paola V
authors.initials: PV
authors.lastname: Plazas
authors.forename: Jessica
authors.initials: J
authors.lastname: Savino
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kracun
authors.forename: María E
authors.initials: ME
authors.lastname: Gomez-Casati
authors.forename: Eleonora
authors.initials: E
authors.lastname: Katz
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Parsons
authors.forename: Neil S
authors.initials: NS
authors.lastname: Millar
authors.forename: Ana B
authors.initials: AB
authors.lastname: Elgoyhen
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D003517:Cyclopentanes / Q000494:pharmacology*; D006199:Hair Cells, Auditory, Inner / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008559:Memantine / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D021122:Protein Subunits / Q000037:antagonists & inhibitors* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D003517:Cyclopentanes; D018733:Nicotinic Antagonists; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; D011994:Recombinant Proteins; C114144:neramexane; D000109:Acetylcholine; D008559:Memantine