Inhibition of the α9α10 nicotinic cholinergic receptor by neramexane, an open channel blocker of N-methyl-d-aspartate 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 α9α10 nicotinic acetylcholine receptors expressed in Xenopus laevis oocytes. We compared its effects with those...
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2007
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00142999_v566_n1-3_p11_Plazas http://hdl.handle.net/20.500.12110/paper_00142999_v566_n1-3_p11_Plazas |
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paper:paper_00142999_v566_n1-3_p11_Plazas2023-06-08T14:36:52Z Inhibition of the α9α10 nicotinic cholinergic receptor by neramexane, an open channel blocker of N-methyl-d-aspartate receptors Plazas, Paola Viviana Gómez Casati, María Eugenia Katz, Eleonora Acetylcholine Hair cells N-methyl-d-aspartate receptor antagonist Neramexane Nicotinic acetylcholine receptors cyclohexane derivative memantine n methyl dextro aspartic acid receptor blocking agent neramexane nicotinic receptor radioligand acetylcholine cyclopentane derivative memantine n methyl dextro aspartic acid receptor neramexane nicotinic receptor nicotinic receptor blocking agent protein subunit recombinant protein Alzheimer disease article cell membrane potential controlled study desensitization drug binding drug inhibition drug potency drug protein binding embryo genetic transfection hair cell human human cell in vivo study kinetics nonhuman oocyte priority journal protein expression rat Xenopus laevis animal cell line drug antagonism drug effect genetics hair cell metabolism physiology Sprague Dawley rat Acetylcholine Animals Cell Line Cyclopentanes Hair Cells, Inner Humans Memantine Nicotinic Antagonists Oocytes Protein Subunits Rats Rats, Sprague-Dawley Receptors, N-Methyl-D-Aspartate Receptors, Nicotinic Recombinant Proteins Xenopus laevis 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. © 2007 Elsevier B.V. All rights reserved. Fil:Plazas, P.V. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Gomez-Casati, M.E. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Katz, E. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2007 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00142999_v566_n1-3_p11_Plazas http://hdl.handle.net/20.500.12110/paper_00142999_v566_n1-3_p11_Plazas |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Acetylcholine Hair cells N-methyl-d-aspartate receptor antagonist Neramexane Nicotinic acetylcholine receptors cyclohexane derivative memantine n methyl dextro aspartic acid receptor blocking agent neramexane nicotinic receptor radioligand acetylcholine cyclopentane derivative memantine n methyl dextro aspartic acid receptor neramexane nicotinic receptor nicotinic receptor blocking agent protein subunit recombinant protein Alzheimer disease article cell membrane potential controlled study desensitization drug binding drug inhibition drug potency drug protein binding embryo genetic transfection hair cell human human cell in vivo study kinetics nonhuman oocyte priority journal protein expression rat Xenopus laevis animal cell line drug antagonism drug effect genetics hair cell metabolism physiology Sprague Dawley rat Acetylcholine Animals Cell Line Cyclopentanes Hair Cells, Inner Humans Memantine Nicotinic Antagonists Oocytes Protein Subunits Rats Rats, Sprague-Dawley Receptors, N-Methyl-D-Aspartate Receptors, Nicotinic Recombinant Proteins Xenopus laevis |
| spellingShingle |
Acetylcholine Hair cells N-methyl-d-aspartate receptor antagonist Neramexane Nicotinic acetylcholine receptors cyclohexane derivative memantine n methyl dextro aspartic acid receptor blocking agent neramexane nicotinic receptor radioligand acetylcholine cyclopentane derivative memantine n methyl dextro aspartic acid receptor neramexane nicotinic receptor nicotinic receptor blocking agent protein subunit recombinant protein Alzheimer disease article cell membrane potential controlled study desensitization drug binding drug inhibition drug potency drug protein binding embryo genetic transfection hair cell human human cell in vivo study kinetics nonhuman oocyte priority journal protein expression rat Xenopus laevis animal cell line drug antagonism drug effect genetics hair cell metabolism physiology Sprague Dawley rat Acetylcholine Animals Cell Line Cyclopentanes Hair Cells, Inner Humans Memantine Nicotinic Antagonists Oocytes Protein Subunits Rats Rats, Sprague-Dawley Receptors, N-Methyl-D-Aspartate Receptors, Nicotinic Recombinant Proteins Xenopus laevis Plazas, Paola Viviana Gómez Casati, María Eugenia Katz, Eleonora Inhibition of the α9α10 nicotinic cholinergic receptor by neramexane, an open channel blocker of N-methyl-d-aspartate receptors |
| topic_facet |
Acetylcholine Hair cells N-methyl-d-aspartate receptor antagonist Neramexane Nicotinic acetylcholine receptors cyclohexane derivative memantine n methyl dextro aspartic acid receptor blocking agent neramexane nicotinic receptor radioligand acetylcholine cyclopentane derivative memantine n methyl dextro aspartic acid receptor neramexane nicotinic receptor nicotinic receptor blocking agent protein subunit recombinant protein Alzheimer disease article cell membrane potential controlled study desensitization drug binding drug inhibition drug potency drug protein binding embryo genetic transfection hair cell human human cell in vivo study kinetics nonhuman oocyte priority journal protein expression rat Xenopus laevis animal cell line drug antagonism drug effect genetics hair cell metabolism physiology Sprague Dawley rat Acetylcholine Animals Cell Line Cyclopentanes Hair Cells, Inner Humans Memantine Nicotinic Antagonists Oocytes Protein Subunits Rats Rats, Sprague-Dawley Receptors, N-Methyl-D-Aspartate Receptors, Nicotinic Recombinant Proteins Xenopus laevis |
| description |
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. © 2007 Elsevier B.V. All rights reserved. |
| author |
Plazas, Paola Viviana Gómez Casati, María Eugenia Katz, Eleonora |
| author_facet |
Plazas, Paola Viviana Gómez Casati, María Eugenia Katz, Eleonora |
| author_sort |
Plazas, Paola Viviana |
| title |
Inhibition of the α9α10 nicotinic cholinergic receptor by neramexane, an open channel blocker of N-methyl-d-aspartate receptors |
| title_short |
Inhibition of the α9α10 nicotinic cholinergic receptor by neramexane, an open channel blocker of N-methyl-d-aspartate receptors |
| title_full |
Inhibition of the α9α10 nicotinic cholinergic receptor by neramexane, an open channel blocker of N-methyl-d-aspartate receptors |
| title_fullStr |
Inhibition of the α9α10 nicotinic cholinergic receptor by neramexane, an open channel blocker of N-methyl-d-aspartate receptors |
| title_full_unstemmed |
Inhibition of the α9α10 nicotinic cholinergic receptor by neramexane, an open channel blocker of N-methyl-d-aspartate receptors |
| title_sort |
inhibition of the α9α10 nicotinic cholinergic receptor by neramexane, an open channel blocker of n-methyl-d-aspartate receptors |
| publishDate |
2007 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00142999_v566_n1-3_p11_Plazas http://hdl.handle.net/20.500.12110/paper_00142999_v566_n1-3_p11_Plazas |
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| _version_ |
1768544349304389632 |