Novel 2-(substituted benzyl)quinuclidines inhibit human α7 and α4β2 nicotinic receptors by different mechanisms

Autores
Arias, Hugo Rubén; López, Jhon J.; Feuerbach, Dominik; Fierro, Angélica; Ortells, Marcelo Oscar; Pérez, Edwin G.
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
This work presents the design and synthesis of a series of novel 2-benzylquinuclidine derivatives, comprising 12 methiodide and 11 hydrochloride salts, and their structural and pharmacological characterization at the human (h) α7 and α4β2 nicotinic receptors (nAChRs). The antagonistic potency of these compounds was tested by Ca2+ influx assays on cells expressing the hα7 or hα4β2 nAChR subtype. To determine the inhibitory mechanisms, additional radioligand binding experiments were performed. The results indicate that the methiodides present the highest affinities for the hα7 nAChR agonist sites, while the same compounds bind preferably to the hα4β2 nAChR ion channel domain. These results indicate that the methiodides are competitive antagonists of the hα7 nAChR but noncompetitive antagonists of the hα4β2 subtype. Docking and molecular dynamics simulations showed that the methiodide derivative 8d binds to the hα7 orthosteric binding sites by forming stable cation-π interactions between the quaternized quinulinuim moiety and the aromatic box in the receptor, whereas compounds 7j and 8j block the hα4β2 AChR ion channel by interacting with a luminal domain formed between the serine (position 6?) and valine (position 13?) rings, that overlaps the imipramine binding site.
Fil: Arias, Hugo Rubén. University of California; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: López, Jhon J.. Pontificia Universidad Católica de Chile; Chile
Fil: Feuerbach, Dominik. Novartis Institutes for Biomedical Research; Suiza
Fil: Fierro, Angélica. Pontificia Universidad Católica de Chile; Chile
Fil: Ortells, Marcelo Oscar. Universidad de Morón. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Pérez, Edwin G.. Pontificia Universidad Católica de Chile; Chile
Materia
Nicotinic Acetylcholine Receptors
Competitive Antagonists
Noncompetitive Antagonists
Quinuclidines
Structure–Activity Relationship
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:11336/24611
Acceder
id CONICETDig_8b9be0053c7f65d199781a3ebcf3fe8d
oai_identifier_str oai:ri.conicet.gov.ar:11336/24611
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Novel 2-(substituted benzyl)quinuclidines inhibit human α7 and α4β2 nicotinic receptors by different mechanismsArias, Hugo RubénLópez, Jhon J.Feuerbach, DominikFierro, AngélicaOrtells, Marcelo OscarPérez, Edwin G.Nicotinic Acetylcholine ReceptorsCompetitive AntagonistsNoncompetitive AntagonistsQuinuclidinesStructure–Activity Relationshiphttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1https://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1This work presents the design and synthesis of a series of novel 2-benzylquinuclidine derivatives, comprising 12 methiodide and 11 hydrochloride salts, and their structural and pharmacological characterization at the human (h) α7 and α4β2 nicotinic receptors (nAChRs). The antagonistic potency of these compounds was tested by Ca2+ influx assays on cells expressing the hα7 or hα4β2 nAChR subtype. To determine the inhibitory mechanisms, additional radioligand binding experiments were performed. The results indicate that the methiodides present the highest affinities for the hα7 nAChR agonist sites, while the same compounds bind preferably to the hα4β2 nAChR ion channel domain. These results indicate that the methiodides are competitive antagonists of the hα7 nAChR but noncompetitive antagonists of the hα4β2 subtype. Docking and molecular dynamics simulations showed that the methiodide derivative 8d binds to the hα7 orthosteric binding sites by forming stable cation-π interactions between the quaternized quinulinuim moiety and the aromatic box in the receptor, whereas compounds 7j and 8j block the hα4β2 AChR ion channel by interacting with a luminal domain formed between the serine (position 6?) and valine (position 13?) rings, that overlaps the imipramine binding site.Fil: Arias, Hugo Rubén. University of California; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: López, Jhon J.. Pontificia Universidad Católica de Chile; ChileFil: Feuerbach, Dominik. Novartis Institutes for Biomedical Research; SuizaFil: Fierro, Angélica. Pontificia Universidad Católica de Chile; ChileFil: Ortells, Marcelo Oscar. Universidad de Morón. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Pérez, Edwin G.. Pontificia Universidad Católica de Chile; ChileElsevier2013-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/24611Arias, Hugo Rubén; López, Jhon J.; Feuerbach, Dominik; Fierro, Angélica; Ortells, Marcelo Oscar; et al.; Novel 2-(substituted benzyl)quinuclidines inhibit human α7 and α4β2 nicotinic receptors by different mechanisms; Elsevier; International Journal Of Biochemistry And Cellular Biology; 45; 11; 8-2013; 2420-24301357-2725CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.biocel.2013.08.003info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S1357272513002562info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-10T13:17:13Zoai:ri.conicet.gov.ar:11336/24611instacron: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:34982025-09-10 13:17:13.844CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Novel 2-(substituted benzyl)quinuclidines inhibit human α7 and α4β2 nicotinic receptors by different mechanisms
title Novel 2-(substituted benzyl)quinuclidines inhibit human α7 and α4β2 nicotinic receptors by different mechanisms
spellingShingle Novel 2-(substituted benzyl)quinuclidines inhibit human α7 and α4β2 nicotinic receptors by different mechanisms
Arias, Hugo Rubén
Nicotinic Acetylcholine Receptors
Competitive Antagonists
Noncompetitive Antagonists
Quinuclidines
Structure–Activity Relationship
title_short Novel 2-(substituted benzyl)quinuclidines inhibit human α7 and α4β2 nicotinic receptors by different mechanisms
title_full Novel 2-(substituted benzyl)quinuclidines inhibit human α7 and α4β2 nicotinic receptors by different mechanisms
title_fullStr Novel 2-(substituted benzyl)quinuclidines inhibit human α7 and α4β2 nicotinic receptors by different mechanisms
title_full_unstemmed Novel 2-(substituted benzyl)quinuclidines inhibit human α7 and α4β2 nicotinic receptors by different mechanisms
title_sort Novel 2-(substituted benzyl)quinuclidines inhibit human α7 and α4β2 nicotinic receptors by different mechanisms
dc.creator.none.fl_str_mv Arias, Hugo Rubén
López, Jhon J.
Feuerbach, Dominik
Fierro, Angélica
Ortells, Marcelo Oscar
Pérez, Edwin G.
author Arias, Hugo Rubén
author_facet Arias, Hugo Rubén
López, Jhon J.
Feuerbach, Dominik
Fierro, Angélica
Ortells, Marcelo Oscar
Pérez, Edwin G.
author_role author
author2 López, Jhon J.
Feuerbach, Dominik
Fierro, Angélica
Ortells, Marcelo Oscar
Pérez, Edwin G.
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Nicotinic Acetylcholine Receptors
Competitive Antagonists
Noncompetitive Antagonists
Quinuclidines
Structure–Activity Relationship
topic Nicotinic Acetylcholine Receptors
Competitive Antagonists
Noncompetitive Antagonists
Quinuclidines
Structure–Activity Relationship
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv This work presents the design and synthesis of a series of novel 2-benzylquinuclidine derivatives, comprising 12 methiodide and 11 hydrochloride salts, and their structural and pharmacological characterization at the human (h) α7 and α4β2 nicotinic receptors (nAChRs). The antagonistic potency of these compounds was tested by Ca2+ influx assays on cells expressing the hα7 or hα4β2 nAChR subtype. To determine the inhibitory mechanisms, additional radioligand binding experiments were performed. The results indicate that the methiodides present the highest affinities for the hα7 nAChR agonist sites, while the same compounds bind preferably to the hα4β2 nAChR ion channel domain. These results indicate that the methiodides are competitive antagonists of the hα7 nAChR but noncompetitive antagonists of the hα4β2 subtype. Docking and molecular dynamics simulations showed that the methiodide derivative 8d binds to the hα7 orthosteric binding sites by forming stable cation-π interactions between the quaternized quinulinuim moiety and the aromatic box in the receptor, whereas compounds 7j and 8j block the hα4β2 AChR ion channel by interacting with a luminal domain formed between the serine (position 6?) and valine (position 13?) rings, that overlaps the imipramine binding site.
Fil: Arias, Hugo Rubén. University of California; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: López, Jhon J.. Pontificia Universidad Católica de Chile; Chile
Fil: Feuerbach, Dominik. Novartis Institutes for Biomedical Research; Suiza
Fil: Fierro, Angélica. Pontificia Universidad Católica de Chile; Chile
Fil: Ortells, Marcelo Oscar. Universidad de Morón. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Pérez, Edwin G.. Pontificia Universidad Católica de Chile; Chile
description This work presents the design and synthesis of a series of novel 2-benzylquinuclidine derivatives, comprising 12 methiodide and 11 hydrochloride salts, and their structural and pharmacological characterization at the human (h) α7 and α4β2 nicotinic receptors (nAChRs). The antagonistic potency of these compounds was tested by Ca2+ influx assays on cells expressing the hα7 or hα4β2 nAChR subtype. To determine the inhibitory mechanisms, additional radioligand binding experiments were performed. The results indicate that the methiodides present the highest affinities for the hα7 nAChR agonist sites, while the same compounds bind preferably to the hα4β2 nAChR ion channel domain. These results indicate that the methiodides are competitive antagonists of the hα7 nAChR but noncompetitive antagonists of the hα4β2 subtype. Docking and molecular dynamics simulations showed that the methiodide derivative 8d binds to the hα7 orthosteric binding sites by forming stable cation-π interactions between the quaternized quinulinuim moiety and the aromatic box in the receptor, whereas compounds 7j and 8j block the hα4β2 AChR ion channel by interacting with a luminal domain formed between the serine (position 6?) and valine (position 13?) rings, that overlaps the imipramine binding site.
publishDate 2013
dc.date.none.fl_str_mv 2013-08
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/11336/24611
Arias, Hugo Rubén; López, Jhon J.; Feuerbach, Dominik; Fierro, Angélica; Ortells, Marcelo Oscar; et al.; Novel 2-(substituted benzyl)quinuclidines inhibit human α7 and α4β2 nicotinic receptors by different mechanisms; Elsevier; International Journal Of Biochemistry And Cellular Biology; 45; 11; 8-2013; 2420-2430
1357-2725
CONICET Digital
CONICET
url http://hdl.handle.net/11336/24611
identifier_str_mv Arias, Hugo Rubén; López, Jhon J.; Feuerbach, Dominik; Fierro, Angélica; Ortells, Marcelo Oscar; et al.; Novel 2-(substituted benzyl)quinuclidines inhibit human α7 and α4β2 nicotinic receptors by different mechanisms; Elsevier; International Journal Of Biochemistry And Cellular Biology; 45; 11; 8-2013; 2420-2430
1357-2725
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.biocel.2013.08.003
info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S1357272513002562
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
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
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 12.993085

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