TY - JOUR
T1 - Inhibition of the α9α10 nicotinic cholinergic receptor by neramexane, an open channel blocker of N-methyl-d-aspartate receptors
AU - Plazas, Paola V.
AU - Savino, Jessica
AU - Kracun, Sebastian
AU - Gomez-Casati, María E.
AU - Katz, Eleonora
AU - Parsons, Christopher G.
AU - Millar, Neil S.
AU - Elgoyhen, Ana B.
PY - 2007/7/2
Y1 - 2007/7/2
N2 - 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 α9α10 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 μM. Finally, clinically-relevant concentrations of neramexane blocked native α9α10-containing nicotinic acetylcholine receptors of rat inner hair cells, thus demonstrating a possible in vivo relevance in potentially unexplored therapeutic areas.
AB - 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 α9α10 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 μM. Finally, clinically-relevant concentrations of neramexane blocked native α9α10-containing nicotinic acetylcholine receptors of rat inner hair cells, thus demonstrating a possible in vivo relevance in potentially unexplored therapeutic areas.
KW - Acetylcholine
KW - Hair cells
KW - N-methyl-d-aspartate receptor antagonist
KW - Neramexane
KW - Nicotinic acetylcholine receptors
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U2 - 10.1016/j.ejphar.2007.03.026
DO - 10.1016/j.ejphar.2007.03.026
M3 - Article
C2 - 17466293
AN - SCOPUS:34249046017
SN - 0014-2999
VL - 566
SP - 11
EP - 19
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1-3
ER -