Novel caffeine analogs as potential leaders on the cholinergic system

Autores
Fabiani, Camila; Biscussi, Brunella; Munafó, Juan Pablo; Salvador, Gabriela Alejandra; Corradi, Jeremias; Murray, Ana Paula; Antollini, Silvia Susana
Año de publicación
2019
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Cholinergic deficit is regarded as an important factor responsible for Alzheimer’s disease symptoms. Two molecular targets for the treatment of this disease are acetylcholinesterase (AChE) and nicotinic receptor (nAChR). We previously demonstrated that caffeine has a dual effect on muscle and a7 nAChRs, behaving as a weak agonist at low concentrations and as a negative modulator at high concentrations. Furthermore, it is wellknown that caffeine also acts as an inhibitor of AChE. The aim of this work was to synthesize more potent caffeine analogs with a dual effect on the cholinergic system by inhibiting AChE and potentiating nAChRs. With this objective, a theophylline fragment, resembling the caffeine chemical structure, was connected with a pyrrole fragment, which is present in the nicotinic chemical structure, through homologation from 3 to 6 carbon atoms (Cn). We first tested the capacity of the different compounds to inhibit the AChE. We found that whether theophylline alone inhibited the enzyme, pyrrolidine did not. With respect to Cn, they all can inhibit the AChE at concentrations of 100, 200, and 400 µM, having C6 the strongest effect. We then explored if theophylline, pyrrolidine, and Cn influence the nAChR conformational state. To this end, we used the AChR conformational-sensitive fluorescence probe crystal violet (CrV) and AChR-rich membranes from Torpedo californica. We found that whether pyrrolidine induced changes in the KD values of CrV taking the nAChR to a state close to the desensitized one at concentrations of 200 and 400 µM, theophylline did not show a significant change in the KD value. The combined analogs also produced changes in the KD values of CrV. This effect was dependent on the length of homologation, being C5 and C6 the most potent analogs with effect at concentrations lower than 50 nM. To understand the molecular mechanism underlying the conformational changes of the nAChR, we expressed adult muscle nAChR in HEK293 cells and performed single-channel recordings with different Cn concentrations. We found that C5 activated muscle nAChR at very low concentrations (from 0.01 pM). At the highest tested concentration (30 µM), we observed a decrease in the mean open duration, which suggests that C5 also acts as an open channel blocker. As a partial conclusion, we can say that we have synthesized more potent caffeine analogs through the combination of caffeine and nicotinic structures. The effect of theophylline on AChE, the effect of pyrrole on AChR, and the effect of Cn on both proteins suggest different pharmacophore profiles for these target molecules. 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. 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: 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: Salvador, Gabriela Alejandra. 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. 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
Congreso de la Sociedad Argentina de Investigación Bioquímica
Salta
Argentina
Sociedad Argentina de Investigación en Bioquímica y Biología Molecular
Panamerican Association for Biochemistry and Molecular Biology
Materia
nicotinic acetylcholine receptor
alzheimer
caffeine analogs
acetylcholinesterase
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:11336/189946
Acceder
id CONICETDig_58c3eec86cdd5be5e720ad2b1efe590c
oai_identifier_str oai:ri.conicet.gov.ar:11336/189946
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Novel caffeine analogs as potential leaders on the cholinergic systemFabiani, CamilaBiscussi, BrunellaMunafó, Juan PabloSalvador, Gabriela AlejandraCorradi, JeremiasMurray, Ana PaulaAntollini, Silvia Susananicotinic acetylcholine receptoralzheimercaffeine analogsacetylcholinesterasehttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Cholinergic deficit is regarded as an important factor responsible for Alzheimer’s disease symptoms. Two molecular targets for the treatment of this disease are acetylcholinesterase (AChE) and nicotinic receptor (nAChR). We previously demonstrated that caffeine has a dual effect on muscle and a7 nAChRs, behaving as a weak agonist at low concentrations and as a negative modulator at high concentrations. Furthermore, it is wellknown that caffeine also acts as an inhibitor of AChE. The aim of this work was to synthesize more potent caffeine analogs with a dual effect on the cholinergic system by inhibiting AChE and potentiating nAChRs. With this objective, a theophylline fragment, resembling the caffeine chemical structure, was connected with a pyrrole fragment, which is present in the nicotinic chemical structure, through homologation from 3 to 6 carbon atoms (Cn). We first tested the capacity of the different compounds to inhibit the AChE. We found that whether theophylline alone inhibited the enzyme, pyrrolidine did not. With respect to Cn, they all can inhibit the AChE at concentrations of 100, 200, and 400 µM, having C6 the strongest effect. We then explored if theophylline, pyrrolidine, and Cn influence the nAChR conformational state. To this end, we used the AChR conformational-sensitive fluorescence probe crystal violet (CrV) and AChR-rich membranes from Torpedo californica. We found that whether pyrrolidine induced changes in the KD values of CrV taking the nAChR to a state close to the desensitized one at concentrations of 200 and 400 µM, theophylline did not show a significant change in the KD value. The combined analogs also produced changes in the KD values of CrV. This effect was dependent on the length of homologation, being C5 and C6 the most potent analogs with effect at concentrations lower than 50 nM. To understand the molecular mechanism underlying the conformational changes of the nAChR, we expressed adult muscle nAChR in HEK293 cells and performed single-channel recordings with different Cn concentrations. We found that C5 activated muscle nAChR at very low concentrations (from 0.01 pM). At the highest tested concentration (30 µM), we observed a decrease in the mean open duration, which suggests that C5 also acts as an open channel blocker. As a partial conclusion, we can say that we have synthesized more potent caffeine analogs through the combination of caffeine and nicotinic structures. The effect of theophylline on AChE, the effect of pyrrole on AChR, and the effect of Cn on both proteins suggest different pharmacophore profiles for these target molecules. 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. 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: 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: Salvador, Gabriela Alejandra. 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. 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; ArgentinaCongreso de la Sociedad Argentina de Investigación BioquímicaSaltaArgentinaSociedad Argentina de Investigación en Bioquímica y Biología MolecularPanamerican Association for Biochemistry and Molecular BiologySociedad Argentina de Investigación en Bioquímica y Biología Molecular2019info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectCongresoJournalhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/189946Novel caffeine analogs as potential leaders on the cholinergic system; Congreso de la Sociedad Argentina de Investigación Bioquímica; Salta; Argentina; 2019; 78-790327-95451669-9106CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://newsite.saib.org.ar/publicaciones/info:eu-repo/semantics/altIdentifier/url/https://saib.org.ar/archivos/biocell-43.pdfInternacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:07:23Zoai:ri.conicet.gov.ar:11336/189946instacron: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 10:07:23.53CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Novel caffeine analogs as potential leaders on the cholinergic system
title Novel caffeine analogs as potential leaders on the cholinergic system
spellingShingle Novel caffeine analogs as potential leaders on the cholinergic system
Fabiani, Camila
nicotinic acetylcholine receptor
alzheimer
caffeine analogs
acetylcholinesterase
title_short Novel caffeine analogs as potential leaders on the cholinergic system
title_full Novel caffeine analogs as potential leaders on the cholinergic system
title_fullStr Novel caffeine analogs as potential leaders on the cholinergic system
title_full_unstemmed Novel caffeine analogs as potential leaders on the cholinergic system
title_sort Novel caffeine analogs as potential leaders on the cholinergic system
dc.creator.none.fl_str_mv Fabiani, Camila
Biscussi, Brunella
Munafó, Juan Pablo
Salvador, Gabriela Alejandra
Corradi, Jeremias
Murray, Ana Paula
Antollini, Silvia Susana
author Fabiani, Camila
author_facet Fabiani, Camila
Biscussi, Brunella
Munafó, Juan Pablo
Salvador, Gabriela Alejandra
Corradi, Jeremias
Murray, Ana Paula
Antollini, Silvia Susana
author_role author
author2 Biscussi, Brunella
Munafó, Juan Pablo
Salvador, Gabriela Alejandra
Corradi, Jeremias
Murray, Ana Paula
Antollini, Silvia Susana
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv nicotinic acetylcholine receptor
alzheimer
caffeine analogs
acetylcholinesterase
topic nicotinic acetylcholine receptor
alzheimer
caffeine analogs
acetylcholinesterase
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 responsible for Alzheimer’s disease symptoms. Two molecular targets for the treatment of this disease are acetylcholinesterase (AChE) and nicotinic receptor (nAChR). We previously demonstrated that caffeine has a dual effect on muscle and a7 nAChRs, behaving as a weak agonist at low concentrations and as a negative modulator at high concentrations. Furthermore, it is wellknown that caffeine also acts as an inhibitor of AChE. The aim of this work was to synthesize more potent caffeine analogs with a dual effect on the cholinergic system by inhibiting AChE and potentiating nAChRs. With this objective, a theophylline fragment, resembling the caffeine chemical structure, was connected with a pyrrole fragment, which is present in the nicotinic chemical structure, through homologation from 3 to 6 carbon atoms (Cn). We first tested the capacity of the different compounds to inhibit the AChE. We found that whether theophylline alone inhibited the enzyme, pyrrolidine did not. With respect to Cn, they all can inhibit the AChE at concentrations of 100, 200, and 400 µM, having C6 the strongest effect. We then explored if theophylline, pyrrolidine, and Cn influence the nAChR conformational state. To this end, we used the AChR conformational-sensitive fluorescence probe crystal violet (CrV) and AChR-rich membranes from Torpedo californica. We found that whether pyrrolidine induced changes in the KD values of CrV taking the nAChR to a state close to the desensitized one at concentrations of 200 and 400 µM, theophylline did not show a significant change in the KD value. The combined analogs also produced changes in the KD values of CrV. This effect was dependent on the length of homologation, being C5 and C6 the most potent analogs with effect at concentrations lower than 50 nM. To understand the molecular mechanism underlying the conformational changes of the nAChR, we expressed adult muscle nAChR in HEK293 cells and performed single-channel recordings with different Cn concentrations. We found that C5 activated muscle nAChR at very low concentrations (from 0.01 pM). At the highest tested concentration (30 µM), we observed a decrease in the mean open duration, which suggests that C5 also acts as an open channel blocker. As a partial conclusion, we can say that we have synthesized more potent caffeine analogs through the combination of caffeine and nicotinic structures. The effect of theophylline on AChE, the effect of pyrrole on AChR, and the effect of Cn on both proteins suggest different pharmacophore profiles for these target molecules. 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. 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: 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: Salvador, Gabriela Alejandra. 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. 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
Congreso de la Sociedad Argentina de Investigación Bioquímica
Salta
Argentina
Sociedad Argentina de Investigación en Bioquímica y Biología Molecular
Panamerican Association for Biochemistry and Molecular Biology
description Cholinergic deficit is regarded as an important factor responsible for Alzheimer’s disease symptoms. Two molecular targets for the treatment of this disease are acetylcholinesterase (AChE) and nicotinic receptor (nAChR). We previously demonstrated that caffeine has a dual effect on muscle and a7 nAChRs, behaving as a weak agonist at low concentrations and as a negative modulator at high concentrations. Furthermore, it is wellknown that caffeine also acts as an inhibitor of AChE. The aim of this work was to synthesize more potent caffeine analogs with a dual effect on the cholinergic system by inhibiting AChE and potentiating nAChRs. With this objective, a theophylline fragment, resembling the caffeine chemical structure, was connected with a pyrrole fragment, which is present in the nicotinic chemical structure, through homologation from 3 to 6 carbon atoms (Cn). We first tested the capacity of the different compounds to inhibit the AChE. We found that whether theophylline alone inhibited the enzyme, pyrrolidine did not. With respect to Cn, they all can inhibit the AChE at concentrations of 100, 200, and 400 µM, having C6 the strongest effect. We then explored if theophylline, pyrrolidine, and Cn influence the nAChR conformational state. To this end, we used the AChR conformational-sensitive fluorescence probe crystal violet (CrV) and AChR-rich membranes from Torpedo californica. We found that whether pyrrolidine induced changes in the KD values of CrV taking the nAChR to a state close to the desensitized one at concentrations of 200 and 400 µM, theophylline did not show a significant change in the KD value. The combined analogs also produced changes in the KD values of CrV. This effect was dependent on the length of homologation, being C5 and C6 the most potent analogs with effect at concentrations lower than 50 nM. To understand the molecular mechanism underlying the conformational changes of the nAChR, we expressed adult muscle nAChR in HEK293 cells and performed single-channel recordings with different Cn concentrations. We found that C5 activated muscle nAChR at very low concentrations (from 0.01 pM). At the highest tested concentration (30 µM), we observed a decrease in the mean open duration, which suggests that C5 also acts as an open channel blocker. As a partial conclusion, we can say that we have synthesized more potent caffeine analogs through the combination of caffeine and nicotinic structures. The effect of theophylline on AChE, the effect of pyrrole on AChR, and the effect of Cn on both proteins suggest different pharmacophore profiles for these target molecules. 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 2019
dc.date.none.fl_str_mv 2019
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dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/189946
Novel caffeine analogs as potential leaders on the cholinergic system; Congreso de la Sociedad Argentina de Investigación Bioquímica; Salta; Argentina; 2019; 78-79
0327-9545
1669-9106
CONICET Digital
CONICET
url http://hdl.handle.net/11336/189946
identifier_str_mv Novel caffeine analogs as potential leaders on the cholinergic system; Congreso de la Sociedad Argentina de Investigación Bioquímica; Salta; Argentina; 2019; 78-79
0327-9545
1669-9106
CONICET Digital
CONICET
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dc.publisher.none.fl_str_mv Sociedad Argentina de Investigación en Bioquímica y Biología Molecular
publisher.none.fl_str_mv Sociedad Argentina de Investigación en Bioquímica y Biología Molecular
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