Design, synthesis and functional evaluation of a novel series of phosphonate-functionalized 1,2,3-triazoles as positive allosteric modulators of α7 nicotinic acetylcholine receptor...
- Autores
- Nielsen, Beatriz Elizabeth; Stabile, Santiago Armando; Vitale, Cristian Alejandro; Bouzat, Cecilia Beatriz
- Año de publicación
- 2020
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel widely distributed in the central nervous system, mainly in hippocampus and cortex. The enhancement of its activity by positive allosteric modulators (PAMs) is a promising therapeutic strategy for cognitive deficits and neurodegenerative disorders. With the aim of developing novel scaffolds with PAM activity, we designed and synthesized a series of phosphonate-functionalized 1,4-disubstituted 1,2,3-triazoles using supported copper nanoparticles as cycloaddition reaction catalyst, and evaluated their activity on α7 receptors by single-channel and whole-cell recordings. We identified several triazole derivatives that displayed PAM activity, the compound functionalized with the methyl phosphonate group being the most efficacious one. At the macroscopic level, α7 potentiation was evidenced as an increase of the maximal currents elicited by acetylcholine with minimal effects on desensitization, recapitulating the actions of type I PAMs. At the single-channel level, the active compounds did not affect channel amplitude, but significantly increased the duration of channel openings and activation episodes. By using chimeric and mutant α7 receptors, we demonstrated that the new α7 PAMs share transmembrane structural determinants of potentiation with other chemically non-related PAMs. To gain further insight into the chemical basis of potentiation, we applied structure-activity relationship strategies involving modification of the chain length, inversion of substituent positions in the triazole ring and changes in the aromatic nucleus. Our findings revealed that the phosphonate-functionalized 1,4-disubstituted 1,2,3-triazole is a novel pharmacophore for the development of therapeutic agents for neurological and neurodegenerative disorders associated to cholinergic dysfunction.
Fil: Nielsen, Beatriz Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Stabile, Santiago Armando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
Fil: Vitale, Cristian Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
Fil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina - Materia
-
NICOTINIC RECEPTORS
LIGAND-GATED ION CHANNELS
PATCH CLAMP
TRIAZOLE
PHOSPHONATES
CLICK CHEMISTRY - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/143117
Ver los metadatos del registro completo
id |
CONICETDig_782550e70dbc447991b50959a386aed2 |
---|---|
oai_identifier_str |
oai:ri.conicet.gov.ar:11336/143117 |
network_acronym_str |
CONICETDig |
repository_id_str |
3498 |
network_name_str |
CONICET Digital (CONICET) |
spelling |
Design, synthesis and functional evaluation of a novel series of phosphonate-functionalized 1,2,3-triazoles as positive allosteric modulators of α7 nicotinic acetylcholine receptorsNielsen, Beatriz ElizabethStabile, Santiago ArmandoVitale, Cristian AlejandroBouzat, Cecilia BeatrizNICOTINIC RECEPTORSLIGAND-GATED ION CHANNELSPATCH CLAMPTRIAZOLEPHOSPHONATESCLICK CHEMISTRYhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel widely distributed in the central nervous system, mainly in hippocampus and cortex. The enhancement of its activity by positive allosteric modulators (PAMs) is a promising therapeutic strategy for cognitive deficits and neurodegenerative disorders. With the aim of developing novel scaffolds with PAM activity, we designed and synthesized a series of phosphonate-functionalized 1,4-disubstituted 1,2,3-triazoles using supported copper nanoparticles as cycloaddition reaction catalyst, and evaluated their activity on α7 receptors by single-channel and whole-cell recordings. We identified several triazole derivatives that displayed PAM activity, the compound functionalized with the methyl phosphonate group being the most efficacious one. At the macroscopic level, α7 potentiation was evidenced as an increase of the maximal currents elicited by acetylcholine with minimal effects on desensitization, recapitulating the actions of type I PAMs. At the single-channel level, the active compounds did not affect channel amplitude, but significantly increased the duration of channel openings and activation episodes. By using chimeric and mutant α7 receptors, we demonstrated that the new α7 PAMs share transmembrane structural determinants of potentiation with other chemically non-related PAMs. To gain further insight into the chemical basis of potentiation, we applied structure-activity relationship strategies involving modification of the chain length, inversion of substituent positions in the triazole ring and changes in the aromatic nucleus. Our findings revealed that the phosphonate-functionalized 1,4-disubstituted 1,2,3-triazole is a novel pharmacophore for the development of therapeutic agents for neurological and neurodegenerative disorders associated to cholinergic dysfunction.Fil: Nielsen, Beatriz Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Stabile, Santiago Armando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Vitale, Cristian Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaAmerican Chemical Society2020-07-28info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/143117Nielsen, Beatriz Elizabeth; Stabile, Santiago Armando; Vitale, Cristian Alejandro; Bouzat, Cecilia Beatriz; Design, synthesis and functional evaluation of a novel series of phosphonate-functionalized 1,2,3-triazoles as positive allosteric modulators of α7 nicotinic acetylcholine receptors; American Chemical Society; ACS Chemical Neuroscience; 11; 17; 28-7-2020; 2688–27041948-7193CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1021/acschemneuro.0c00348info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/acschemneuro.0c00348info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:23:48Zoai:ri.conicet.gov.ar:11336/143117instacron: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 10:23:48.418CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Design, synthesis and functional evaluation of a novel series of phosphonate-functionalized 1,2,3-triazoles as positive allosteric modulators of α7 nicotinic acetylcholine receptors |
title |
Design, synthesis and functional evaluation of a novel series of phosphonate-functionalized 1,2,3-triazoles as positive allosteric modulators of α7 nicotinic acetylcholine receptors |
spellingShingle |
Design, synthesis and functional evaluation of a novel series of phosphonate-functionalized 1,2,3-triazoles as positive allosteric modulators of α7 nicotinic acetylcholine receptors Nielsen, Beatriz Elizabeth NICOTINIC RECEPTORS LIGAND-GATED ION CHANNELS PATCH CLAMP TRIAZOLE PHOSPHONATES CLICK CHEMISTRY |
title_short |
Design, synthesis and functional evaluation of a novel series of phosphonate-functionalized 1,2,3-triazoles as positive allosteric modulators of α7 nicotinic acetylcholine receptors |
title_full |
Design, synthesis and functional evaluation of a novel series of phosphonate-functionalized 1,2,3-triazoles as positive allosteric modulators of α7 nicotinic acetylcholine receptors |
title_fullStr |
Design, synthesis and functional evaluation of a novel series of phosphonate-functionalized 1,2,3-triazoles as positive allosteric modulators of α7 nicotinic acetylcholine receptors |
title_full_unstemmed |
Design, synthesis and functional evaluation of a novel series of phosphonate-functionalized 1,2,3-triazoles as positive allosteric modulators of α7 nicotinic acetylcholine receptors |
title_sort |
Design, synthesis and functional evaluation of a novel series of phosphonate-functionalized 1,2,3-triazoles as positive allosteric modulators of α7 nicotinic acetylcholine receptors |
dc.creator.none.fl_str_mv |
Nielsen, Beatriz Elizabeth Stabile, Santiago Armando Vitale, Cristian Alejandro Bouzat, Cecilia Beatriz |
author |
Nielsen, Beatriz Elizabeth |
author_facet |
Nielsen, Beatriz Elizabeth Stabile, Santiago Armando Vitale, Cristian Alejandro Bouzat, Cecilia Beatriz |
author_role |
author |
author2 |
Stabile, Santiago Armando Vitale, Cristian Alejandro Bouzat, Cecilia Beatriz |
author2_role |
author author author |
dc.subject.none.fl_str_mv |
NICOTINIC RECEPTORS LIGAND-GATED ION CHANNELS PATCH CLAMP TRIAZOLE PHOSPHONATES CLICK CHEMISTRY |
topic |
NICOTINIC RECEPTORS LIGAND-GATED ION CHANNELS PATCH CLAMP TRIAZOLE PHOSPHONATES CLICK CHEMISTRY |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 |
dc.description.none.fl_txt_mv |
The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel widely distributed in the central nervous system, mainly in hippocampus and cortex. The enhancement of its activity by positive allosteric modulators (PAMs) is a promising therapeutic strategy for cognitive deficits and neurodegenerative disorders. With the aim of developing novel scaffolds with PAM activity, we designed and synthesized a series of phosphonate-functionalized 1,4-disubstituted 1,2,3-triazoles using supported copper nanoparticles as cycloaddition reaction catalyst, and evaluated their activity on α7 receptors by single-channel and whole-cell recordings. We identified several triazole derivatives that displayed PAM activity, the compound functionalized with the methyl phosphonate group being the most efficacious one. At the macroscopic level, α7 potentiation was evidenced as an increase of the maximal currents elicited by acetylcholine with minimal effects on desensitization, recapitulating the actions of type I PAMs. At the single-channel level, the active compounds did not affect channel amplitude, but significantly increased the duration of channel openings and activation episodes. By using chimeric and mutant α7 receptors, we demonstrated that the new α7 PAMs share transmembrane structural determinants of potentiation with other chemically non-related PAMs. To gain further insight into the chemical basis of potentiation, we applied structure-activity relationship strategies involving modification of the chain length, inversion of substituent positions in the triazole ring and changes in the aromatic nucleus. Our findings revealed that the phosphonate-functionalized 1,4-disubstituted 1,2,3-triazole is a novel pharmacophore for the development of therapeutic agents for neurological and neurodegenerative disorders associated to cholinergic dysfunction. Fil: Nielsen, Beatriz Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina Fil: Stabile, Santiago Armando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina Fil: Vitale, Cristian Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina Fil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina |
description |
The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel widely distributed in the central nervous system, mainly in hippocampus and cortex. The enhancement of its activity by positive allosteric modulators (PAMs) is a promising therapeutic strategy for cognitive deficits and neurodegenerative disorders. With the aim of developing novel scaffolds with PAM activity, we designed and synthesized a series of phosphonate-functionalized 1,4-disubstituted 1,2,3-triazoles using supported copper nanoparticles as cycloaddition reaction catalyst, and evaluated their activity on α7 receptors by single-channel and whole-cell recordings. We identified several triazole derivatives that displayed PAM activity, the compound functionalized with the methyl phosphonate group being the most efficacious one. At the macroscopic level, α7 potentiation was evidenced as an increase of the maximal currents elicited by acetylcholine with minimal effects on desensitization, recapitulating the actions of type I PAMs. At the single-channel level, the active compounds did not affect channel amplitude, but significantly increased the duration of channel openings and activation episodes. By using chimeric and mutant α7 receptors, we demonstrated that the new α7 PAMs share transmembrane structural determinants of potentiation with other chemically non-related PAMs. To gain further insight into the chemical basis of potentiation, we applied structure-activity relationship strategies involving modification of the chain length, inversion of substituent positions in the triazole ring and changes in the aromatic nucleus. Our findings revealed that the phosphonate-functionalized 1,4-disubstituted 1,2,3-triazole is a novel pharmacophore for the development of therapeutic agents for neurological and neurodegenerative disorders associated to cholinergic dysfunction. |
publishDate |
2020 |
dc.date.none.fl_str_mv |
2020-07-28 |
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/11336/143117 Nielsen, Beatriz Elizabeth; Stabile, Santiago Armando; Vitale, Cristian Alejandro; Bouzat, Cecilia Beatriz; Design, synthesis and functional evaluation of a novel series of phosphonate-functionalized 1,2,3-triazoles as positive allosteric modulators of α7 nicotinic acetylcholine receptors; American Chemical Society; ACS Chemical Neuroscience; 11; 17; 28-7-2020; 2688–2704 1948-7193 CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/143117 |
identifier_str_mv |
Nielsen, Beatriz Elizabeth; Stabile, Santiago Armando; Vitale, Cristian Alejandro; Bouzat, Cecilia Beatriz; Design, synthesis and functional evaluation of a novel series of phosphonate-functionalized 1,2,3-triazoles as positive allosteric modulators of α7 nicotinic acetylcholine receptors; American Chemical Society; ACS Chemical Neuroscience; 11; 17; 28-7-2020; 2688–2704 1948-7193 CONICET Digital CONICET |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/doi/10.1021/acschemneuro.0c00348 info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/acschemneuro.0c00348 |
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 |
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 |
_version_ |
1844614233718784000 |
score |
13.070432 |