Modulation of the cholinergic system by synthetic derivatives of caffeine

Autores
Fabiani, Camila; Biscussi, Brunella; Munafó, Juan Pablo; Murray, Ana Paula; Corradi, Jeremias; Antollini, Silvia Susana
Año de publicación
2020
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Cholinergic deficit is regarded as an important factor in Alzheimer’s disease. Two molecular targets for its treatment are the acetylcholinesterase (AChE) and the nicotinic receptor (nAChR). We previously demonstrated that caffeine acts on nAChRs as a weak agonist and it is known that it inhibits AChE. Here, we synthetized more potent bifunctional caffeine derivatives or analogs. A theophylline fragment was connected with a pyrrole fragment through homologation from 3 to 7 carbon atoms to form the compounds C3 to C7 (Cn). We found that all Cn inhibited the AChE, having C 7 the strongest effect. To explore if the analogs influence the nAChR conformational state, the nAChR conformational-sensitive probe crystal violet (CrV) and nAChR-rich membranes from T. californica were used. The analogs produced changes in the KD values of CrV, being C5 and C6 the most potent. To understand the molecular mechanism underlying these conformational changes, we recorded single-channel events from the muscle nAChR. We observed that all the compounds activated muscle nAChR at low concentrations and the activation was as isolated openings even at the highest Cn concentrations. Thus, our results demonstrate that the new compounds behave as dual modulators by acting as AChE inhibitors and as wick nAChR agonists. To gain insights about the molecular interaction of these compounds with both receptors we performed in-silico studies. Our results bring new information about the mechanism of modulation of pharmacologic targets for the design of new therapies for the intervention in neurological diseases.
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
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: 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
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: Corradi, Jeremias. 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: 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
Primeras Jornadas Virtuales de la Sociedad Argentina de Biofísica
Virtual
Argentina
Sociedad Argentina de Biofísíca
Materia
receptor de acetilcolina
Enf. de Alzheimer
cafeina
biofisica
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:11336/188140
Acceder
id CONICETDig_263fa95870ac3e40468cabb9af24e3c2
oai_identifier_str oai:ri.conicet.gov.ar:11336/188140
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Modulation of the cholinergic system by synthetic derivatives of caffeineFabiani, CamilaBiscussi, BrunellaMunafó, Juan PabloMurray, Ana PaulaCorradi, JeremiasAntollini, Silvia Susanareceptor de acetilcolinaEnf. de Alzheimercafeinabiofisicahttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Cholinergic deficit is regarded as an important factor in Alzheimer’s disease. Two molecular targets for its treatment are the acetylcholinesterase (AChE) and the nicotinic receptor (nAChR). We previously demonstrated that caffeine acts on nAChRs as a weak agonist and it is known that it inhibits AChE. Here, we synthetized more potent bifunctional caffeine derivatives or analogs. A theophylline fragment was connected with a pyrrole fragment through homologation from 3 to 7 carbon atoms to form the compounds C3 to C7 (Cn). We found that all Cn inhibited the AChE, having C 7 the strongest effect. To explore if the analogs influence the nAChR conformational state, the nAChR conformational-sensitive probe crystal violet (CrV) and nAChR-rich membranes from T. californica were used. The analogs produced changes in the KD values of CrV, being C5 and C6 the most potent. To understand the molecular mechanism underlying these conformational changes, we recorded single-channel events from the muscle nAChR. We observed that all the compounds activated muscle nAChR at low concentrations and the activation was as isolated openings even at the highest Cn concentrations. Thus, our results demonstrate that the new compounds behave as dual modulators by acting as AChE inhibitors and as wick nAChR agonists. To gain insights about the molecular interaction of these compounds with both receptors we performed in-silico studies. Our results bring new information about the mechanism of modulation of pharmacologic targets for the design of new therapies for the intervention in neurological diseases.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; 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: 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; 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: Corradi, Jeremias. 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: 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; ArgentinaPrimeras Jornadas Virtuales de la Sociedad Argentina de BiofísicaVirtualArgentinaSociedad Argentina de BiofísícaSociedad Argentina de Biofísica2020info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectJornadaBookhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/188140Modulation of the cholinergic system by synthetic derivatives of caffeine; Primeras Jornadas Virtuales de la Sociedad Argentina de Biofísica; Virtual; Argentina; 2020; 44-44978-987-27591-8-6CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://biofisica.org.ar/reuniones-cientificas/reunionsab-previas/Internacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:53:48Zoai:ri.conicet.gov.ar:11336/188140instacron: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:34982025-09-03 09:53:49.077CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Modulation of the cholinergic system by synthetic derivatives of caffeine
title Modulation of the cholinergic system by synthetic derivatives of caffeine
spellingShingle Modulation of the cholinergic system by synthetic derivatives of caffeine
Fabiani, Camila
receptor de acetilcolina
Enf. de Alzheimer
cafeina
biofisica
title_short Modulation of the cholinergic system by synthetic derivatives of caffeine
title_full Modulation of the cholinergic system by synthetic derivatives of caffeine
title_fullStr Modulation of the cholinergic system by synthetic derivatives of caffeine
title_full_unstemmed Modulation of the cholinergic system by synthetic derivatives of caffeine
title_sort Modulation of the cholinergic system by synthetic derivatives of caffeine
dc.creator.none.fl_str_mv Fabiani, Camila
Biscussi, Brunella
Munafó, Juan Pablo
Murray, Ana Paula
Corradi, Jeremias
Antollini, Silvia Susana
author Fabiani, Camila
author_facet Fabiani, Camila
Biscussi, Brunella
Munafó, Juan Pablo
Murray, Ana Paula
Corradi, Jeremias
Antollini, Silvia Susana
author_role author
author2 Biscussi, Brunella
Munafó, Juan Pablo
Murray, Ana Paula
Corradi, Jeremias
Antollini, Silvia Susana
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv receptor de acetilcolina
Enf. de Alzheimer
cafeina
biofisica
topic receptor de acetilcolina
Enf. de Alzheimer
cafeina
biofisica
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 regarded as an important factor in Alzheimer’s disease. Two molecular targets for its treatment are the acetylcholinesterase (AChE) and the nicotinic receptor (nAChR). We previously demonstrated that caffeine acts on nAChRs as a weak agonist and it is known that it inhibits AChE. Here, we synthetized more potent bifunctional caffeine derivatives or analogs. A theophylline fragment was connected with a pyrrole fragment through homologation from 3 to 7 carbon atoms to form the compounds C3 to C7 (Cn). We found that all Cn inhibited the AChE, having C 7 the strongest effect. To explore if the analogs influence the nAChR conformational state, the nAChR conformational-sensitive probe crystal violet (CrV) and nAChR-rich membranes from T. californica were used. The analogs produced changes in the KD values of CrV, being C5 and C6 the most potent. To understand the molecular mechanism underlying these conformational changes, we recorded single-channel events from the muscle nAChR. We observed that all the compounds activated muscle nAChR at low concentrations and the activation was as isolated openings even at the highest Cn concentrations. Thus, our results demonstrate that the new compounds behave as dual modulators by acting as AChE inhibitors and as wick nAChR agonists. To gain insights about the molecular interaction of these compounds with both receptors we performed in-silico studies. Our results bring new information about the mechanism of modulation of pharmacologic targets for the design of new therapies for the intervention in neurological diseases.
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
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: 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
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: Corradi, Jeremias. 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: 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
Primeras Jornadas Virtuales de la Sociedad Argentina de Biofísica
Virtual
Argentina
Sociedad Argentina de Biofísíca
description Cholinergic deficit is regarded as an important factor in Alzheimer’s disease. Two molecular targets for its treatment are the acetylcholinesterase (AChE) and the nicotinic receptor (nAChR). We previously demonstrated that caffeine acts on nAChRs as a weak agonist and it is known that it inhibits AChE. Here, we synthetized more potent bifunctional caffeine derivatives or analogs. A theophylline fragment was connected with a pyrrole fragment through homologation from 3 to 7 carbon atoms to form the compounds C3 to C7 (Cn). We found that all Cn inhibited the AChE, having C 7 the strongest effect. To explore if the analogs influence the nAChR conformational state, the nAChR conformational-sensitive probe crystal violet (CrV) and nAChR-rich membranes from T. californica were used. The analogs produced changes in the KD values of CrV, being C5 and C6 the most potent. To understand the molecular mechanism underlying these conformational changes, we recorded single-channel events from the muscle nAChR. We observed that all the compounds activated muscle nAChR at low concentrations and the activation was as isolated openings even at the highest Cn concentrations. Thus, our results demonstrate that the new compounds behave as dual modulators by acting as AChE inhibitors and as wick nAChR agonists. To gain insights about the molecular interaction of these compounds with both receptors we performed in-silico studies. Our results bring new information about the mechanism of modulation of pharmacologic targets for the design of new therapies for the intervention in neurological diseases.
publishDate 2020
dc.date.none.fl_str_mv 2020
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/conferenceObject
Jornada
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/11336/188140
Modulation of the cholinergic system by synthetic derivatives of caffeine; Primeras Jornadas Virtuales de la Sociedad Argentina de Biofísica; Virtual; Argentina; 2020; 44-44
978-987-27591-8-6
CONICET Digital
CONICET
url http://hdl.handle.net/11336/188140
identifier_str_mv Modulation of the cholinergic system by synthetic derivatives of caffeine; Primeras Jornadas Virtuales de la Sociedad Argentina de Biofísica; Virtual; Argentina; 2020; 44-44
978-987-27591-8-6
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
dc.coverage.none.fl_str_mv Internacional
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)
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_ 1842269249359314944
score 13.13397

Publicaciones similares