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

Autores
Plazas, Paola Viviana; Savino, Jessica; Kracun, Sebastian; Gomez Casati, Maria Eugenia; Katz, Eleonora; Parsons, Christopher G.; Millar, Neil S.; Elgoyhen, Ana Belen
Año de publicación
2007
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Plazas, Paola Viviana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Savino, Jessica. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Kracun, Sebastian. University College London; Estados Unidos
Fil: Gomez Casati, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Katz, Eleonora. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina
Fil: Parsons, Christopher G.. Merz Pharmaceuticals GmbH; Alemania
Fil: Millar, Neil S.. University College London; Estados Unidos
Fil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentina
Materia
Acetylcholine
Hair Cells
N-Methyl-D-Aspartate Receptor Antagonist
Neramexane
Nicotinic Acetylcholine Receptors
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/79674
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/79674
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Inhibition of the α9α10 nicotinic cholinergic receptor by neramexane, an open channel blocker of N-methyl-d-aspartate receptorsPlazas, Paola VivianaSavino, JessicaKracun, SebastianGomez Casati, Maria EugeniaKatz, EleonoraParsons, Christopher G.Millar, Neil S.Elgoyhen, Ana BelenAcetylcholineHair CellsN-Methyl-D-Aspartate Receptor AntagonistNeramexaneNicotinic Acetylcholine Receptorshttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1In 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.Fil: Plazas, Paola Viviana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Savino, Jessica. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Kracun, Sebastian. University College London; Estados UnidosFil: Gomez Casati, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Katz, Eleonora. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; ArgentinaFil: Parsons, Christopher G.. Merz Pharmaceuticals GmbH; AlemaniaFil: Millar, Neil S.. University College London; Estados UnidosFil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; ArgentinaElsevier Science2007-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/79674Plazas, Paola Viviana; Savino, Jessica; Kracun, Sebastian; Gomez Casati, Maria Eugenia; Katz, Eleonora; et al.; Inhibition of the α9α10 nicotinic cholinergic receptor by neramexane, an open channel blocker of N-methyl-d-aspartate receptors; Elsevier Science; European Journal of Pharmacology; 566; 1-3; 7-2007; 11-190014-2999CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pubmed/17466293info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ejphar.2007.03.026info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S001429990700341Xinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:03:02Zoai:ri.conicet.gov.ar:11336/79674instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 10:03:02.743CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Inhibition of the α9α10 nicotinic cholinergic receptor by neramexane, an open channel blocker of N-methyl-d-aspartate receptors
title Inhibition of the α9α10 nicotinic cholinergic receptor by neramexane, an open channel blocker of N-methyl-d-aspartate receptors
spellingShingle Inhibition of the α9α10 nicotinic cholinergic receptor by neramexane, an open channel blocker of N-methyl-d-aspartate receptors
Plazas, Paola Viviana
Acetylcholine
Hair Cells
N-Methyl-D-Aspartate Receptor Antagonist
Neramexane
Nicotinic Acetylcholine 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
dc.creator.none.fl_str_mv Plazas, Paola Viviana
Savino, Jessica
Kracun, Sebastian
Gomez Casati, Maria Eugenia
Katz, Eleonora
Parsons, Christopher G.
Millar, Neil S.
Elgoyhen, Ana Belen
author Plazas, Paola Viviana
author_facet Plazas, Paola Viviana
Savino, Jessica
Kracun, Sebastian
Gomez Casati, Maria Eugenia
Katz, Eleonora
Parsons, Christopher G.
Millar, Neil S.
Elgoyhen, Ana Belen
author_role author
author2 Savino, Jessica
Kracun, Sebastian
Gomez Casati, Maria Eugenia
Katz, Eleonora
Parsons, Christopher G.
Millar, Neil S.
Elgoyhen, Ana Belen
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Acetylcholine
Hair Cells
N-Methyl-D-Aspartate Receptor Antagonist
Neramexane
Nicotinic Acetylcholine Receptors
topic Acetylcholine
Hair Cells
N-Methyl-D-Aspartate Receptor Antagonist
Neramexane
Nicotinic Acetylcholine Receptors
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv 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.
Fil: Plazas, Paola Viviana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Savino, Jessica. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Kracun, Sebastian. University College London; Estados Unidos
Fil: Gomez Casati, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Katz, Eleonora. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina
Fil: Parsons, Christopher G.. Merz Pharmaceuticals GmbH; Alemania
Fil: Millar, Neil S.. University College London; Estados Unidos
Fil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentina
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.
publishDate 2007
dc.date.none.fl_str_mv 2007-07
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/79674
Plazas, Paola Viviana; Savino, Jessica; Kracun, Sebastian; Gomez Casati, Maria Eugenia; Katz, Eleonora; et al.; Inhibition of the α9α10 nicotinic cholinergic receptor by neramexane, an open channel blocker of N-methyl-d-aspartate receptors; Elsevier Science; European Journal of Pharmacology; 566; 1-3; 7-2007; 11-19
0014-2999
CONICET Digital
CONICET
url http://hdl.handle.net/11336/79674
identifier_str_mv Plazas, Paola Viviana; Savino, Jessica; Kracun, Sebastian; Gomez Casati, Maria Eugenia; Katz, Eleonora; et al.; Inhibition of the α9α10 nicotinic cholinergic receptor by neramexane, an open channel blocker of N-methyl-d-aspartate receptors; Elsevier Science; European Journal of Pharmacology; 566; 1-3; 7-2007; 11-19
0014-2999
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pubmed/17466293
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ejphar.2007.03.026
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S001429990700341X
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier Science
publisher.none.fl_str_mv Elsevier Science
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.885934

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