Repurposing of Clinical Drugs as Negative Allosteric Modulators for the Human 5-HT3A Receptor

Autores
Rodriguez Araujo, Noelia; Bergé, Ignacio; Corradi, Jeremias; Bouzat Cecilia
Año de publicación
2024
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Drug repurposing offers a rational approach to reducing the time and costs associated with developing new therapies. In this study, piperazine (PZE), an anthelmintic drug, and hydroxyzine (HZE), a first-generation H1 receptor antagonist and derivative of PZE, were evaluated as novel modulators of the human 5-HT3A receptor. This receptor belongs to pentameric ligand-gated ion channel family and has gained interest as a pharmacological target for neurological, psychiatric, and gastrointestinal disorders. HEK293 cells were transfected with 5-HT3A receptor cDNA, and electrophysiological analyses were subsequently conducted. Whole-cell recordings revealed that preincubation with PZE or HZE inhibited 5-HT-evoked currents in 5-HT3A receptors, with HZE showing greater potency than PZE. Notably, co-application of either compound with 5-HT did not alter the peak current, suggesting a non-competitive inhibition mechanism. PZE also increased the EC50 value and reduced the maximum 5-HT response, supporting as a negative allosteric modulator (NAM). Molecular docking studies further indicated two primary binding sites for PZE and HZE within the 5-HT3A receptor, separate from the 5-HT binding site, supporting their roles as potential NAMs. These binding sites were identified at the interface between the transmembrane (TMD) and the extracellular domains, as well as at the top of the TMD. Based on the potential interactions of the drugs with the residues, two amino acids were selected from each binding site and were mutated to confirm their contribution. For the first analyzed mutant, a change in the inhibition mediated by HZE was detected, thus suggesting its contribution to the allosteric modulation. This drug repurposing strategy provides a rational and efficient pathway to explore new therapeutic applications for clinically approved drugs by identifying alternative targets and their mechanisms.
Fil: Rodriguez Araujo, Noelia. 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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Bergé, Ignacio. 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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Corradi, Jeremias. New College Of Florida; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Bouzat Cecilia. 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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
LII Reunión Anual de la Sociedad Argentina de Biofísica
Bahia Blanca
Argentina
Sociedad Argentina de Biofísica
Materia
REPURPOSING
PIPERAZINE
5-HT3
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:11336/273725
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/273725
network_acronym_str CONICETDig
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network_name_str CONICET Digital (CONICET)
spelling Repurposing of Clinical Drugs as Negative Allosteric Modulators for the Human 5-HT3A ReceptorRodriguez Araujo, NoeliaBergé, IgnacioCorradi, JeremiasBouzat CeciliaREPURPOSINGPIPERAZINE5-HT3https://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Drug repurposing offers a rational approach to reducing the time and costs associated with developing new therapies. In this study, piperazine (PZE), an anthelmintic drug, and hydroxyzine (HZE), a first-generation H1 receptor antagonist and derivative of PZE, were evaluated as novel modulators of the human 5-HT3A receptor. This receptor belongs to pentameric ligand-gated ion channel family and has gained interest as a pharmacological target for neurological, psychiatric, and gastrointestinal disorders. HEK293 cells were transfected with 5-HT3A receptor cDNA, and electrophysiological analyses were subsequently conducted. Whole-cell recordings revealed that preincubation with PZE or HZE inhibited 5-HT-evoked currents in 5-HT3A receptors, with HZE showing greater potency than PZE. Notably, co-application of either compound with 5-HT did not alter the peak current, suggesting a non-competitive inhibition mechanism. PZE also increased the EC50 value and reduced the maximum 5-HT response, supporting as a negative allosteric modulator (NAM). Molecular docking studies further indicated two primary binding sites for PZE and HZE within the 5-HT3A receptor, separate from the 5-HT binding site, supporting their roles as potential NAMs. These binding sites were identified at the interface between the transmembrane (TMD) and the extracellular domains, as well as at the top of the TMD. Based on the potential interactions of the drugs with the residues, two amino acids were selected from each binding site and were mutated to confirm their contribution. For the first analyzed mutant, a change in the inhibition mediated by HZE was detected, thus suggesting its contribution to the allosteric modulation. This drug repurposing strategy provides a rational and efficient pathway to explore new therapeutic applications for clinically approved drugs by identifying alternative targets and their mechanisms.Fil: Rodriguez Araujo, Noelia. 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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Bergé, Ignacio. 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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Corradi, Jeremias. New College Of Florida; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bouzat Cecilia. 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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaLII Reunión Anual de la Sociedad Argentina de BiofísicaBahia BlancaArgentinaSociedad Argentina de BiofísicaSociedad Argentina de BiofísicaRivas, Gabriela LeonorVazquez, Diego SebastianCelej, Maria Soledad2024info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectCongresoBookhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/273725Repurposing of Clinical Drugs as Negative Allosteric Modulators for the Human 5-HT3A Receptor; LII Reunión Anual de la Sociedad Argentina de Biofísica; Bahia Blanca; Argentina; 2024; 61-61CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://biofisica.org.ar/congreso-2024/#resumenesNacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:05:45Zoai:ri.conicet.gov.ar:11336/273725instacron: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:34982025-10-22 11:05:46.227CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Repurposing of Clinical Drugs as Negative Allosteric Modulators for the Human 5-HT3A Receptor
title Repurposing of Clinical Drugs as Negative Allosteric Modulators for the Human 5-HT3A Receptor
spellingShingle Repurposing of Clinical Drugs as Negative Allosteric Modulators for the Human 5-HT3A Receptor
Rodriguez Araujo, Noelia
REPURPOSING
PIPERAZINE
5-HT3
title_short Repurposing of Clinical Drugs as Negative Allosteric Modulators for the Human 5-HT3A Receptor
title_full Repurposing of Clinical Drugs as Negative Allosteric Modulators for the Human 5-HT3A Receptor
title_fullStr Repurposing of Clinical Drugs as Negative Allosteric Modulators for the Human 5-HT3A Receptor
title_full_unstemmed Repurposing of Clinical Drugs as Negative Allosteric Modulators for the Human 5-HT3A Receptor
title_sort Repurposing of Clinical Drugs as Negative Allosteric Modulators for the Human 5-HT3A Receptor
dc.creator.none.fl_str_mv Rodriguez Araujo, Noelia
Bergé, Ignacio
Corradi, Jeremias
Bouzat Cecilia
author Rodriguez Araujo, Noelia
author_facet Rodriguez Araujo, Noelia
Bergé, Ignacio
Corradi, Jeremias
Bouzat Cecilia
author_role author
author2 Bergé, Ignacio
Corradi, Jeremias
Bouzat Cecilia
author2_role author
author
author
dc.contributor.none.fl_str_mv Rivas, Gabriela Leonor
Vazquez, Diego Sebastian
Celej, Maria Soledad
dc.subject.none.fl_str_mv REPURPOSING
PIPERAZINE
5-HT3
topic REPURPOSING
PIPERAZINE
5-HT3
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Drug repurposing offers a rational approach to reducing the time and costs associated with developing new therapies. In this study, piperazine (PZE), an anthelmintic drug, and hydroxyzine (HZE), a first-generation H1 receptor antagonist and derivative of PZE, were evaluated as novel modulators of the human 5-HT3A receptor. This receptor belongs to pentameric ligand-gated ion channel family and has gained interest as a pharmacological target for neurological, psychiatric, and gastrointestinal disorders. HEK293 cells were transfected with 5-HT3A receptor cDNA, and electrophysiological analyses were subsequently conducted. Whole-cell recordings revealed that preincubation with PZE or HZE inhibited 5-HT-evoked currents in 5-HT3A receptors, with HZE showing greater potency than PZE. Notably, co-application of either compound with 5-HT did not alter the peak current, suggesting a non-competitive inhibition mechanism. PZE also increased the EC50 value and reduced the maximum 5-HT response, supporting as a negative allosteric modulator (NAM). Molecular docking studies further indicated two primary binding sites for PZE and HZE within the 5-HT3A receptor, separate from the 5-HT binding site, supporting their roles as potential NAMs. These binding sites were identified at the interface between the transmembrane (TMD) and the extracellular domains, as well as at the top of the TMD. Based on the potential interactions of the drugs with the residues, two amino acids were selected from each binding site and were mutated to confirm their contribution. For the first analyzed mutant, a change in the inhibition mediated by HZE was detected, thus suggesting its contribution to the allosteric modulation. This drug repurposing strategy provides a rational and efficient pathway to explore new therapeutic applications for clinically approved drugs by identifying alternative targets and their mechanisms.
Fil: Rodriguez Araujo, Noelia. 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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Bergé, Ignacio. 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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Corradi, Jeremias. New College Of Florida; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Bouzat Cecilia. 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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
LII Reunión Anual de la Sociedad Argentina de Biofísica
Bahia Blanca
Argentina
Sociedad Argentina de Biofísica
description Drug repurposing offers a rational approach to reducing the time and costs associated with developing new therapies. In this study, piperazine (PZE), an anthelmintic drug, and hydroxyzine (HZE), a first-generation H1 receptor antagonist and derivative of PZE, were evaluated as novel modulators of the human 5-HT3A receptor. This receptor belongs to pentameric ligand-gated ion channel family and has gained interest as a pharmacological target for neurological, psychiatric, and gastrointestinal disorders. HEK293 cells were transfected with 5-HT3A receptor cDNA, and electrophysiological analyses were subsequently conducted. Whole-cell recordings revealed that preincubation with PZE or HZE inhibited 5-HT-evoked currents in 5-HT3A receptors, with HZE showing greater potency than PZE. Notably, co-application of either compound with 5-HT did not alter the peak current, suggesting a non-competitive inhibition mechanism. PZE also increased the EC50 value and reduced the maximum 5-HT response, supporting as a negative allosteric modulator (NAM). Molecular docking studies further indicated two primary binding sites for PZE and HZE within the 5-HT3A receptor, separate from the 5-HT binding site, supporting their roles as potential NAMs. These binding sites were identified at the interface between the transmembrane (TMD) and the extracellular domains, as well as at the top of the TMD. Based on the potential interactions of the drugs with the residues, two amino acids were selected from each binding site and were mutated to confirm their contribution. For the first analyzed mutant, a change in the inhibition mediated by HZE was detected, thus suggesting its contribution to the allosteric modulation. This drug repurposing strategy provides a rational and efficient pathway to explore new therapeutic applications for clinically approved drugs by identifying alternative targets and their mechanisms.
publishDate 2024
dc.date.none.fl_str_mv 2024
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/conferenceObject
Congreso
Book
http://purl.org/coar/resource_type/c_5794
info:ar-repo/semantics/documentoDeConferencia
status_str publishedVersion
format conferenceObject
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/273725
Repurposing of Clinical Drugs as Negative Allosteric Modulators for the Human 5-HT3A Receptor; LII Reunión Anual de la Sociedad Argentina de Biofísica; Bahia Blanca; Argentina; 2024; 61-61
CONICET Digital
CONICET
url http://hdl.handle.net/11336/273725
identifier_str_mv Repurposing of Clinical Drugs as Negative Allosteric Modulators for the Human 5-HT3A Receptor; LII Reunión Anual de la Sociedad Argentina de Biofísica; Bahia Blanca; Argentina; 2024; 61-61
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://biofisica.org.ar/congreso-2024/#resumenes
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
dc.coverage.none.fl_str_mv Nacional
dc.publisher.none.fl_str_mv Sociedad Argentina de Biofísica
publisher.none.fl_str_mv Sociedad Argentina de Biofísica
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
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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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