Drimane Sesquiterpenoids Noncompetitively Inhibit Human α4β2 Nicotinic Acetylcholine Receptors with Higher Potency Compared to Human α3β4 and α7 Subtypes

Autores
Arias, Hugo Rubén; Feuerbach, Dominik; Schmidt, Bernd; Heydenreich, Matthias; Paz, Cristian; Ortells, Marcelo Oscar
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The drimane sesquiterpenoids drimenin, cinnamolide, dendocarbin A, and polygodial were purified from the Canelo tree (Drimys winteri) and chemically characterized by spectroscopic methods. The pharmacological activity of these natural compounds were determined on hα4β2, hα3β4, and hα7 nicotinic acetylcholine receptors (AChRs) by Ca2+ influx measurements. The results established that drimane sesquiterpenoids inhibit AChRs with the following selectivity: hα4β2 > hα3β4 > hα7. In the case of hα4β2 AChRs, the following potency rank order was determined (IC50's in μM): drimenin (0.97 ± 0.35) > cinnamolide (1.57 ± 0.36) > polygodial (62.5 ± 19.9) dendocarbin A (no activity). To determine putative structural features underlying the differences in inhibitory potency at hα4β2 AChRs, additional structure-activity relationship and molecular docking experiments were performed. The Ca2+ influx and structural results supported a noncompetitive mechanism of inhibition, where drimenin interacted with luminal and nonluminal (TMD-β2 intrasubunit) sites. The structure-activity relationship results, i.e., the lower the ligand polarity, the higher the inhibitory potency, supported the nonluminal interaction. Ligand binding to both sites might inhibit the hα4β2 AChR by a cooperative mechanism, as shown experimentally (nH > 1). Drimenin could be used as a molecular scaffold for the development of more potent inhibitors with higher selectivity for the hα4β2 AChR.
Fil: Arias, Hugo Rubén. California Northstate University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Feuerbach, Dominik. Novartis Institutes for Biomedical Research; Suiza
Fil: Schmidt, Bernd. Universitat Potsdam; Alemania
Fil: Heydenreich, Matthias. Universitat Potsdam; Alemania
Fil: Paz, Cristian. Universidad de La Frontera; Chile
Fil: Ortells, Marcelo Oscar. Universidad de Morón; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Materia
Nicotinic Receptor
Drimane Sesquiterpenoids
Inhibitor
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:11336/72261
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/72261
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Drimane Sesquiterpenoids Noncompetitively Inhibit Human α4β2 Nicotinic Acetylcholine Receptors with Higher Potency Compared to Human α3β4 and α7 SubtypesArias, Hugo RubénFeuerbach, DominikSchmidt, BerndHeydenreich, MatthiasPaz, CristianOrtells, Marcelo OscarNicotinic ReceptorDrimane SesquiterpenoidsInhibitorhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3The drimane sesquiterpenoids drimenin, cinnamolide, dendocarbin A, and polygodial were purified from the Canelo tree (Drimys winteri) and chemically characterized by spectroscopic methods. The pharmacological activity of these natural compounds were determined on hα4β2, hα3β4, and hα7 nicotinic acetylcholine receptors (AChRs) by Ca2+ influx measurements. The results established that drimane sesquiterpenoids inhibit AChRs with the following selectivity: hα4β2 > hα3β4 > hα7. In the case of hα4β2 AChRs, the following potency rank order was determined (IC50's in μM): drimenin (0.97 ± 0.35) > cinnamolide (1.57 ± 0.36) > polygodial (62.5 ± 19.9) dendocarbin A (no activity). To determine putative structural features underlying the differences in inhibitory potency at hα4β2 AChRs, additional structure-activity relationship and molecular docking experiments were performed. The Ca2+ influx and structural results supported a noncompetitive mechanism of inhibition, where drimenin interacted with luminal and nonluminal (TMD-β2 intrasubunit) sites. The structure-activity relationship results, i.e., the lower the ligand polarity, the higher the inhibitory potency, supported the nonluminal interaction. Ligand binding to both sites might inhibit the hα4β2 AChR by a cooperative mechanism, as shown experimentally (nH > 1). Drimenin could be used as a molecular scaffold for the development of more potent inhibitors with higher selectivity for the hα4β2 AChR.Fil: Arias, Hugo Rubén. California Northstate University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Feuerbach, Dominik. Novartis Institutes for Biomedical Research; SuizaFil: Schmidt, Bernd. Universitat Potsdam; AlemaniaFil: Heydenreich, Matthias. Universitat Potsdam; AlemaniaFil: Paz, Cristian. Universidad de La Frontera; ChileFil: Ortells, Marcelo Oscar. Universidad de Morón; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaAmerican Chemical Society2018-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/72261Arias, Hugo Rubén; Feuerbach, Dominik; Schmidt, Bernd; Heydenreich, Matthias; Paz, Cristian; et al.; Drimane Sesquiterpenoids Noncompetitively Inhibit Human α4β2 Nicotinic Acetylcholine Receptors with Higher Potency Compared to Human α3β4 and α7 Subtypes; American Chemical Society; Journal of Natural Products; 81; 4; 4-2018; 811-8170163-3864CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://pubs.acs.org/doi/10.1021/acs.jnatprod.7b00893info:eu-repo/semantics/altIdentifier/doi/10.1021/acs.jnatprod.7b00893info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:35:33Zoai:ri.conicet.gov.ar:11336/72261instacron: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:34982025-09-29 09:35:34.067CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Drimane Sesquiterpenoids Noncompetitively Inhibit Human α4β2 Nicotinic Acetylcholine Receptors with Higher Potency Compared to Human α3β4 and α7 Subtypes
title Drimane Sesquiterpenoids Noncompetitively Inhibit Human α4β2 Nicotinic Acetylcholine Receptors with Higher Potency Compared to Human α3β4 and α7 Subtypes
spellingShingle Drimane Sesquiterpenoids Noncompetitively Inhibit Human α4β2 Nicotinic Acetylcholine Receptors with Higher Potency Compared to Human α3β4 and α7 Subtypes
Arias, Hugo Rubén
Nicotinic Receptor
Drimane Sesquiterpenoids
Inhibitor
title_short Drimane Sesquiterpenoids Noncompetitively Inhibit Human α4β2 Nicotinic Acetylcholine Receptors with Higher Potency Compared to Human α3β4 and α7 Subtypes
title_full Drimane Sesquiterpenoids Noncompetitively Inhibit Human α4β2 Nicotinic Acetylcholine Receptors with Higher Potency Compared to Human α3β4 and α7 Subtypes
title_fullStr Drimane Sesquiterpenoids Noncompetitively Inhibit Human α4β2 Nicotinic Acetylcholine Receptors with Higher Potency Compared to Human α3β4 and α7 Subtypes
title_full_unstemmed Drimane Sesquiterpenoids Noncompetitively Inhibit Human α4β2 Nicotinic Acetylcholine Receptors with Higher Potency Compared to Human α3β4 and α7 Subtypes
title_sort Drimane Sesquiterpenoids Noncompetitively Inhibit Human α4β2 Nicotinic Acetylcholine Receptors with Higher Potency Compared to Human α3β4 and α7 Subtypes
dc.creator.none.fl_str_mv Arias, Hugo Rubén
Feuerbach, Dominik
Schmidt, Bernd
Heydenreich, Matthias
Paz, Cristian
Ortells, Marcelo Oscar
author Arias, Hugo Rubén
author_facet Arias, Hugo Rubén
Feuerbach, Dominik
Schmidt, Bernd
Heydenreich, Matthias
Paz, Cristian
Ortells, Marcelo Oscar
author_role author
author2 Feuerbach, Dominik
Schmidt, Bernd
Heydenreich, Matthias
Paz, Cristian
Ortells, Marcelo Oscar
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Nicotinic Receptor
Drimane Sesquiterpenoids
Inhibitor
topic Nicotinic Receptor
Drimane Sesquiterpenoids
Inhibitor
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv The drimane sesquiterpenoids drimenin, cinnamolide, dendocarbin A, and polygodial were purified from the Canelo tree (Drimys winteri) and chemically characterized by spectroscopic methods. The pharmacological activity of these natural compounds were determined on hα4β2, hα3β4, and hα7 nicotinic acetylcholine receptors (AChRs) by Ca2+ influx measurements. The results established that drimane sesquiterpenoids inhibit AChRs with the following selectivity: hα4β2 > hα3β4 > hα7. In the case of hα4β2 AChRs, the following potency rank order was determined (IC50's in μM): drimenin (0.97 ± 0.35) > cinnamolide (1.57 ± 0.36) > polygodial (62.5 ± 19.9) dendocarbin A (no activity). To determine putative structural features underlying the differences in inhibitory potency at hα4β2 AChRs, additional structure-activity relationship and molecular docking experiments were performed. The Ca2+ influx and structural results supported a noncompetitive mechanism of inhibition, where drimenin interacted with luminal and nonluminal (TMD-β2 intrasubunit) sites. The structure-activity relationship results, i.e., the lower the ligand polarity, the higher the inhibitory potency, supported the nonluminal interaction. Ligand binding to both sites might inhibit the hα4β2 AChR by a cooperative mechanism, as shown experimentally (nH > 1). Drimenin could be used as a molecular scaffold for the development of more potent inhibitors with higher selectivity for the hα4β2 AChR.
Fil: Arias, Hugo Rubén. California Northstate University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Feuerbach, Dominik. Novartis Institutes for Biomedical Research; Suiza
Fil: Schmidt, Bernd. Universitat Potsdam; Alemania
Fil: Heydenreich, Matthias. Universitat Potsdam; Alemania
Fil: Paz, Cristian. Universidad de La Frontera; Chile
Fil: Ortells, Marcelo Oscar. Universidad de Morón; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
description The drimane sesquiterpenoids drimenin, cinnamolide, dendocarbin A, and polygodial were purified from the Canelo tree (Drimys winteri) and chemically characterized by spectroscopic methods. The pharmacological activity of these natural compounds were determined on hα4β2, hα3β4, and hα7 nicotinic acetylcholine receptors (AChRs) by Ca2+ influx measurements. The results established that drimane sesquiterpenoids inhibit AChRs with the following selectivity: hα4β2 > hα3β4 > hα7. In the case of hα4β2 AChRs, the following potency rank order was determined (IC50's in μM): drimenin (0.97 ± 0.35) > cinnamolide (1.57 ± 0.36) > polygodial (62.5 ± 19.9) dendocarbin A (no activity). To determine putative structural features underlying the differences in inhibitory potency at hα4β2 AChRs, additional structure-activity relationship and molecular docking experiments were performed. The Ca2+ influx and structural results supported a noncompetitive mechanism of inhibition, where drimenin interacted with luminal and nonluminal (TMD-β2 intrasubunit) sites. The structure-activity relationship results, i.e., the lower the ligand polarity, the higher the inhibitory potency, supported the nonluminal interaction. Ligand binding to both sites might inhibit the hα4β2 AChR by a cooperative mechanism, as shown experimentally (nH > 1). Drimenin could be used as a molecular scaffold for the development of more potent inhibitors with higher selectivity for the hα4β2 AChR.
publishDate 2018
dc.date.none.fl_str_mv 2018-04
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/11336/72261
Arias, Hugo Rubén; Feuerbach, Dominik; Schmidt, Bernd; Heydenreich, Matthias; Paz, Cristian; et al.; Drimane Sesquiterpenoids Noncompetitively Inhibit Human α4β2 Nicotinic Acetylcholine Receptors with Higher Potency Compared to Human α3β4 and α7 Subtypes; American Chemical Society; Journal of Natural Products; 81; 4; 4-2018; 811-817
0163-3864
CONICET Digital
CONICET
url http://hdl.handle.net/11336/72261
identifier_str_mv Arias, Hugo Rubén; Feuerbach, Dominik; Schmidt, Bernd; Heydenreich, Matthias; Paz, Cristian; et al.; Drimane Sesquiterpenoids Noncompetitively Inhibit Human α4β2 Nicotinic Acetylcholine Receptors with Higher Potency Compared to Human α3β4 and α7 Subtypes; American Chemical Society; Journal of Natural Products; 81; 4; 4-2018; 811-817
0163-3864
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://pubs.acs.org/doi/10.1021/acs.jnatprod.7b00893
info:eu-repo/semantics/altIdentifier/doi/10.1021/acs.jnatprod.7b00893
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 American Chemical Society
publisher.none.fl_str_mv American Chemical Society
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 13.070432

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