New multitarget molecules derived from caffeine as modulators of the cholinergic system

Autores
Munafó, Juan Pablo; Biscussi, Brunella; Fabiani, Camila; Obiol, Diego Javier; Costabel, Marcelo Daniel; Bouzat, Cecilia Beatriz; Murray, Ana Paula; Antollini, Silvia Susana
Año de publicación
2022
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Cholinergic deficit is a characteristic factor of Alzheimer's disease. Two possible molecular targets for its treatment are the acetylcholinesterase (AChE) and the nicotinic acetylcholine receptors (nAChR). In previous studies, we found that caffeine behaves as a partial nAChR agonist and confirmed that it inhibits AChE. Based on these findings, in this work we obtained 8 more potent bifunctional derivatives for these molecular targets. They consisted of a theophylline ring connected to several chemical groups (pyrrole, piperidine, methylpiperazine, or diethylamine) by different linkers (linear chains of 5 and 7 carbon atoms (C5 and C7) or C3-NH-C2 and C5-NH-C2 chains). All of them were more potent AChE inhibitors than caffeine. Electrophysiological studies by single-channel measurements in adult muscle nAChR transiently expressed in BOSC23 cells showed that all compounds, except C5 and C7 diethylamine, activated the nAChR, being C7-piperidine the most active. To understand the molecular mechanism underlying receptor activation, we further explored whether these analogs influence the conformational state of nAChR using nAChR-rich membranes of T. californica and crystal violet (CrV), a sensitive probe for the conformation of nAChRs. We observed that only C5-piperidine stabilized the nAChR in a desensitized state. Finally, we carried out in silico studies on AChE and nAChR (with its loop C partially closed) to obtain information on the molecular interactions among these compounds and both molecular targets. Altogether, our results show that the new synthetized compounds can inhibit the AChE and activate the nAChR with greater potency than caffeine and provide further information on the modulation mechanisms of pharmacological targets for the design of novel therapeutic interventions in neurological diseases.
Fil: Munafó, Juan Pablo. 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: Biscussi, Brunella. 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: Fabiani, Camila. 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: Obiol, Diego Javier. Universidad Nacional del Sur. Departamento de Física; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Costabel, Marcelo Daniel. Universidad Nacional del Sur. Departamento de Física; 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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Murray, Ana Paula. 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: Antollini, Silvia Susana. 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
L Reunión Anual de la Sociedad Argentina de Biofísica
Rosario
Argentina
Sociedad Argentina de Biofísica
Materia
nicotinic acetylcholine receptor
acetylcholinesterase
alzhemeir disease
caffeine
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:11336/205956
Acceder
id CONICETDig_fea043e67219e19bdfe1a94f0d53ade1
oai_identifier_str oai:ri.conicet.gov.ar:11336/205956
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling New multitarget molecules derived from caffeine as modulators of the cholinergic systemMunafó, Juan PabloBiscussi, BrunellaFabiani, CamilaObiol, Diego JavierCostabel, Marcelo DanielBouzat, Cecilia BeatrizMurray, Ana PaulaAntollini, Silvia Susananicotinic acetylcholine receptoracetylcholinesterasealzhemeir diseasecaffeinehttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Cholinergic deficit is a characteristic factor of Alzheimer's disease. Two possible molecular targets for its treatment are the acetylcholinesterase (AChE) and the nicotinic acetylcholine receptors (nAChR). In previous studies, we found that caffeine behaves as a partial nAChR agonist and confirmed that it inhibits AChE. Based on these findings, in this work we obtained 8 more potent bifunctional derivatives for these molecular targets. They consisted of a theophylline ring connected to several chemical groups (pyrrole, piperidine, methylpiperazine, or diethylamine) by different linkers (linear chains of 5 and 7 carbon atoms (C5 and C7) or C3-NH-C2 and C5-NH-C2 chains). All of them were more potent AChE inhibitors than caffeine. Electrophysiological studies by single-channel measurements in adult muscle nAChR transiently expressed in BOSC23 cells showed that all compounds, except C5 and C7 diethylamine, activated the nAChR, being C7-piperidine the most active. To understand the molecular mechanism underlying receptor activation, we further explored whether these analogs influence the conformational state of nAChR using nAChR-rich membranes of T. californica and crystal violet (CrV), a sensitive probe for the conformation of nAChRs. We observed that only C5-piperidine stabilized the nAChR in a desensitized state. Finally, we carried out in silico studies on AChE and nAChR (with its loop C partially closed) to obtain information on the molecular interactions among these compounds and both molecular targets. Altogether, our results show that the new synthetized compounds can inhibit the AChE and activate the nAChR with greater potency than caffeine and provide further information on the modulation mechanisms of pharmacological targets for the design of novel therapeutic interventions in neurological diseases.Fil: Munafó, Juan Pablo. 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: Biscussi, Brunella. 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: Fabiani, Camila. 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: Obiol, Diego Javier. Universidad Nacional del Sur. Departamento de Física; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Costabel, Marcelo Daniel. Universidad Nacional del Sur. Departamento de Física; 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; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Murray, Ana Paula. 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: Antollini, Silvia Susana. 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; ArgentinaL Reunión Anual de la Sociedad Argentina de BiofísicaRosarioArgentinaSociedad Argentina de BiofísicaSociedad Argentina de BiofísicaAmbroggio, Ernesto EstebanCelej, Maria Soledad2022info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectReuniónBookhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/205956New multitarget molecules derived from caffeine as modulators of the cholinergic system; L Reunión Anual de la Sociedad Argentina de Biofísica; Rosario; Argentina; 2022; 87-87978-987-48938-0-2CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://biofisica.org.ar/reuniones-cientificas/reunionsab-previas/Nacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-12-23T14:46:13Zoai:ri.conicet.gov.ar:11336/205956instacron: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:34982025-12-23 14:46:14.152CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv New multitarget molecules derived from caffeine as modulators of the cholinergic system
title New multitarget molecules derived from caffeine as modulators of the cholinergic system
spellingShingle New multitarget molecules derived from caffeine as modulators of the cholinergic system
Munafó, Juan Pablo
nicotinic acetylcholine receptor
acetylcholinesterase
alzhemeir disease
caffeine
title_short New multitarget molecules derived from caffeine as modulators of the cholinergic system
title_full New multitarget molecules derived from caffeine as modulators of the cholinergic system
title_fullStr New multitarget molecules derived from caffeine as modulators of the cholinergic system
title_full_unstemmed New multitarget molecules derived from caffeine as modulators of the cholinergic system
title_sort New multitarget molecules derived from caffeine as modulators of the cholinergic system
dc.creator.none.fl_str_mv Munafó, Juan Pablo
Biscussi, Brunella
Fabiani, Camila
Obiol, Diego Javier
Costabel, Marcelo Daniel
Bouzat, Cecilia Beatriz
Murray, Ana Paula
Antollini, Silvia Susana
author Munafó, Juan Pablo
author_facet Munafó, Juan Pablo
Biscussi, Brunella
Fabiani, Camila
Obiol, Diego Javier
Costabel, Marcelo Daniel
Bouzat, Cecilia Beatriz
Murray, Ana Paula
Antollini, Silvia Susana
author_role author
author2 Biscussi, Brunella
Fabiani, Camila
Obiol, Diego Javier
Costabel, Marcelo Daniel
Bouzat, Cecilia Beatriz
Murray, Ana Paula
Antollini, Silvia Susana
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ambroggio, Ernesto Esteban
Celej, Maria Soledad
dc.subject.none.fl_str_mv nicotinic acetylcholine receptor
acetylcholinesterase
alzhemeir disease
caffeine
topic nicotinic acetylcholine receptor
acetylcholinesterase
alzhemeir disease
caffeine
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Cholinergic deficit is a characteristic factor of Alzheimer's disease. Two possible molecular targets for its treatment are the acetylcholinesterase (AChE) and the nicotinic acetylcholine receptors (nAChR). In previous studies, we found that caffeine behaves as a partial nAChR agonist and confirmed that it inhibits AChE. Based on these findings, in this work we obtained 8 more potent bifunctional derivatives for these molecular targets. They consisted of a theophylline ring connected to several chemical groups (pyrrole, piperidine, methylpiperazine, or diethylamine) by different linkers (linear chains of 5 and 7 carbon atoms (C5 and C7) or C3-NH-C2 and C5-NH-C2 chains). All of them were more potent AChE inhibitors than caffeine. Electrophysiological studies by single-channel measurements in adult muscle nAChR transiently expressed in BOSC23 cells showed that all compounds, except C5 and C7 diethylamine, activated the nAChR, being C7-piperidine the most active. To understand the molecular mechanism underlying receptor activation, we further explored whether these analogs influence the conformational state of nAChR using nAChR-rich membranes of T. californica and crystal violet (CrV), a sensitive probe for the conformation of nAChRs. We observed that only C5-piperidine stabilized the nAChR in a desensitized state. Finally, we carried out in silico studies on AChE and nAChR (with its loop C partially closed) to obtain information on the molecular interactions among these compounds and both molecular targets. Altogether, our results show that the new synthetized compounds can inhibit the AChE and activate the nAChR with greater potency than caffeine and provide further information on the modulation mechanisms of pharmacological targets for the design of novel therapeutic interventions in neurological diseases.
Fil: Munafó, Juan Pablo. 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: Biscussi, Brunella. 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: Fabiani, Camila. 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: Obiol, Diego Javier. Universidad Nacional del Sur. Departamento de Física; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Costabel, Marcelo Daniel. Universidad Nacional del Sur. Departamento de Física; 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. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Murray, Ana Paula. 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: Antollini, Silvia Susana. 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
L Reunión Anual de la Sociedad Argentina de Biofísica
Rosario
Argentina
Sociedad Argentina de Biofísica
description Cholinergic deficit is a characteristic factor of Alzheimer's disease. Two possible molecular targets for its treatment are the acetylcholinesterase (AChE) and the nicotinic acetylcholine receptors (nAChR). In previous studies, we found that caffeine behaves as a partial nAChR agonist and confirmed that it inhibits AChE. Based on these findings, in this work we obtained 8 more potent bifunctional derivatives for these molecular targets. They consisted of a theophylline ring connected to several chemical groups (pyrrole, piperidine, methylpiperazine, or diethylamine) by different linkers (linear chains of 5 and 7 carbon atoms (C5 and C7) or C3-NH-C2 and C5-NH-C2 chains). All of them were more potent AChE inhibitors than caffeine. Electrophysiological studies by single-channel measurements in adult muscle nAChR transiently expressed in BOSC23 cells showed that all compounds, except C5 and C7 diethylamine, activated the nAChR, being C7-piperidine the most active. To understand the molecular mechanism underlying receptor activation, we further explored whether these analogs influence the conformational state of nAChR using nAChR-rich membranes of T. californica and crystal violet (CrV), a sensitive probe for the conformation of nAChRs. We observed that only C5-piperidine stabilized the nAChR in a desensitized state. Finally, we carried out in silico studies on AChE and nAChR (with its loop C partially closed) to obtain information on the molecular interactions among these compounds and both molecular targets. Altogether, our results show that the new synthetized compounds can inhibit the AChE and activate the nAChR with greater potency than caffeine and provide further information on the modulation mechanisms of pharmacological targets for the design of novel therapeutic interventions in neurological diseases.
publishDate 2022
dc.date.none.fl_str_mv 2022
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/conferenceObject
Reunión
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/11336/205956
New multitarget molecules derived from caffeine as modulators of the cholinergic system; L Reunión Anual de la Sociedad Argentina de Biofísica; Rosario; Argentina; 2022; 87-87
978-987-48938-0-2
CONICET Digital
CONICET
url http://hdl.handle.net/11336/205956
identifier_str_mv New multitarget molecules derived from caffeine as modulators of the cholinergic system; L Reunión Anual de la Sociedad Argentina de Biofísica; Rosario; Argentina; 2022; 87-87
978-987-48938-0-2
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/reuniones-cientificas/reunionsab-previas/
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
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
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instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
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repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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