Synthesis, biological evaluation and in silico analysis of new methylxanthine derivatives as potentiators of the cholinergic system.

Autores
Munafó, Juan Pablo; Biscussi, Brunella; Gundin, Santiago Jorge; Obiol, Diego Javier; Costabel, Marcelo Daniel; Bouzat, Cecilia Beatriz; Murray, Ana Paula; Antollini, Silvia Susana
Año de publicación
2024
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Cholinergic deficiency is commonly associated with several diseases, such as Alzheimer's and Myasthenia Gravis. To address this question, one of the strategies involves the synthesis of hybrid molecules that integrate different pharmacophores. In previous research, caffeine was used as a basis to create caffeine-pyrrolidine hybrids, which were shown to be effective both as acetylcholinesterase (AChE) inhibitors and in potentiating the nicotinic acetylcholine receptor (nAChR). In the present study, a new series of caffeine derivatives with various primary and secondary amines as accessory groups were evaluated. These compounds were efficiently synthesized using a microwave reactor, with alkylbrominated intermediates of theophylline and theobromine as starting reagents along with the corresponding amine. All methylxanthine hybrids were found to be AChE inhibitors, with some exhibiting potency comparable to that of tacrine. To assess the impact of these compounds on the nAChR, fluorescence spectroscopy and single-channel measurements were performed to evaluate their effects on the receptor's conformational state and functionality. Some of the compounds acted as partial agonists, although not all were capable of stabilizing the receptor in a desensitized state. To understand the molecular mechanisms underlying these results, we conducted molecular docking studies on both AChE and nAChR. The agonist activity of the synthesized caffeine analogs on the nAChR was found to depend on the accessory group, while the stabilization of the receptor in a desensitized state was associated with interactions involving the intermediate chain of the hybrid compounds at the binding site. Thus, we obtained a group of molecules that behave as cholinergic potentiators more efficiently than caffeine and also identified key features crucial for modulating the pharmacological targets under study.
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: Gundin, Santiago Jorge. 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: Obiol, Diego Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; Argentina
Fil: Costabel, Marcelo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física 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. 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
LVI Reunión Anual de la Asociación Argentina de Farmacología Experimental
Bahía Blanca
Argentina
Asociación Argentina de Farmacología Experimental
Materia
Cholinergic signaling
acetylcholinesterase
nicotinic acetylcholine receptor
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:11336/277771
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/277771
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Synthesis, biological evaluation and in silico analysis of new methylxanthine derivatives as potentiators of the cholinergic system.Munafó, Juan PabloBiscussi, BrunellaGundin, Santiago JorgeObiol, Diego JavierCostabel, Marcelo DanielBouzat, Cecilia BeatrizMurray, Ana PaulaAntollini, Silvia SusanaCholinergic signalingacetylcholinesterasenicotinic acetylcholine receptorcaffeinehttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Cholinergic deficiency is commonly associated with several diseases, such as Alzheimer's and Myasthenia Gravis. To address this question, one of the strategies involves the synthesis of hybrid molecules that integrate different pharmacophores. In previous research, caffeine was used as a basis to create caffeine-pyrrolidine hybrids, which were shown to be effective both as acetylcholinesterase (AChE) inhibitors and in potentiating the nicotinic acetylcholine receptor (nAChR). In the present study, a new series of caffeine derivatives with various primary and secondary amines as accessory groups were evaluated. These compounds were efficiently synthesized using a microwave reactor, with alkylbrominated intermediates of theophylline and theobromine as starting reagents along with the corresponding amine. All methylxanthine hybrids were found to be AChE inhibitors, with some exhibiting potency comparable to that of tacrine. To assess the impact of these compounds on the nAChR, fluorescence spectroscopy and single-channel measurements were performed to evaluate their effects on the receptor's conformational state and functionality. Some of the compounds acted as partial agonists, although not all were capable of stabilizing the receptor in a desensitized state. To understand the molecular mechanisms underlying these results, we conducted molecular docking studies on both AChE and nAChR. The agonist activity of the synthesized caffeine analogs on the nAChR was found to depend on the accessory group, while the stabilization of the receptor in a desensitized state was associated with interactions involving the intermediate chain of the hybrid compounds at the binding site. Thus, we obtained a group of molecules that behave as cholinergic potentiators more efficiently than caffeine and also identified key features crucial for modulating the pharmacological targets under study.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: Gundin, Santiago Jorge. 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: Obiol, Diego Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; ArgentinaFil: Costabel, Marcelo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física 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; 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; ArgentinaLVI Reunión Anual de la Asociación Argentina de Farmacología ExperimentalBahía BlancaArgentinaAsociación Argentina de Farmacología ExperimentalAsociación Argentina De Farmacología Experimental2024info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectReuniónBookhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/277771Synthesis, biological evaluation and in silico analysis of new methylxanthine derivatives as potentiators of the cholinergic system.; LVI Reunión Anual de la Asociación Argentina de Farmacología Experimental; Bahía Blanca; Argentina; 2024; 51-51978-631-90806-0-5CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://aafeargentina.org/congresos-aafe/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 Técnicas2025-12-17T15:12:37Zoai:ri.conicet.gov.ar:11336/277771instacron: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:34982025-12-17 15:12:38.22CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Synthesis, biological evaluation and in silico analysis of new methylxanthine derivatives as potentiators of the cholinergic system.
title Synthesis, biological evaluation and in silico analysis of new methylxanthine derivatives as potentiators of the cholinergic system.
spellingShingle Synthesis, biological evaluation and in silico analysis of new methylxanthine derivatives as potentiators of the cholinergic system.
Munafó, Juan Pablo
Cholinergic signaling
acetylcholinesterase
nicotinic acetylcholine receptor
caffeine
title_short Synthesis, biological evaluation and in silico analysis of new methylxanthine derivatives as potentiators of the cholinergic system.
title_full Synthesis, biological evaluation and in silico analysis of new methylxanthine derivatives as potentiators of the cholinergic system.
title_fullStr Synthesis, biological evaluation and in silico analysis of new methylxanthine derivatives as potentiators of the cholinergic system.
title_full_unstemmed Synthesis, biological evaluation and in silico analysis of new methylxanthine derivatives as potentiators of the cholinergic system.
title_sort Synthesis, biological evaluation and in silico analysis of new methylxanthine derivatives as potentiators of the cholinergic system.
dc.creator.none.fl_str_mv Munafó, Juan Pablo
Biscussi, Brunella
Gundin, Santiago Jorge
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
Gundin, Santiago Jorge
Obiol, Diego Javier
Costabel, Marcelo Daniel
Bouzat, Cecilia Beatriz
Murray, Ana Paula
Antollini, Silvia Susana
author_role author
author2 Biscussi, Brunella
Gundin, Santiago Jorge
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.subject.none.fl_str_mv Cholinergic signaling
acetylcholinesterase
nicotinic acetylcholine receptor
caffeine
topic Cholinergic signaling
acetylcholinesterase
nicotinic acetylcholine receptor
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 deficiency is commonly associated with several diseases, such as Alzheimer's and Myasthenia Gravis. To address this question, one of the strategies involves the synthesis of hybrid molecules that integrate different pharmacophores. In previous research, caffeine was used as a basis to create caffeine-pyrrolidine hybrids, which were shown to be effective both as acetylcholinesterase (AChE) inhibitors and in potentiating the nicotinic acetylcholine receptor (nAChR). In the present study, a new series of caffeine derivatives with various primary and secondary amines as accessory groups were evaluated. These compounds were efficiently synthesized using a microwave reactor, with alkylbrominated intermediates of theophylline and theobromine as starting reagents along with the corresponding amine. All methylxanthine hybrids were found to be AChE inhibitors, with some exhibiting potency comparable to that of tacrine. To assess the impact of these compounds on the nAChR, fluorescence spectroscopy and single-channel measurements were performed to evaluate their effects on the receptor's conformational state and functionality. Some of the compounds acted as partial agonists, although not all were capable of stabilizing the receptor in a desensitized state. To understand the molecular mechanisms underlying these results, we conducted molecular docking studies on both AChE and nAChR. The agonist activity of the synthesized caffeine analogs on the nAChR was found to depend on the accessory group, while the stabilization of the receptor in a desensitized state was associated with interactions involving the intermediate chain of the hybrid compounds at the binding site. Thus, we obtained a group of molecules that behave as cholinergic potentiators more efficiently than caffeine and also identified key features crucial for modulating the pharmacological targets under study.
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: Gundin, Santiago Jorge. 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: Obiol, Diego Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; Argentina
Fil: Costabel, Marcelo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física 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. 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
LVI Reunión Anual de la Asociación Argentina de Farmacología Experimental
Bahía Blanca
Argentina
Asociación Argentina de Farmacología Experimental
description Cholinergic deficiency is commonly associated with several diseases, such as Alzheimer's and Myasthenia Gravis. To address this question, one of the strategies involves the synthesis of hybrid molecules that integrate different pharmacophores. In previous research, caffeine was used as a basis to create caffeine-pyrrolidine hybrids, which were shown to be effective both as acetylcholinesterase (AChE) inhibitors and in potentiating the nicotinic acetylcholine receptor (nAChR). In the present study, a new series of caffeine derivatives with various primary and secondary amines as accessory groups were evaluated. These compounds were efficiently synthesized using a microwave reactor, with alkylbrominated intermediates of theophylline and theobromine as starting reagents along with the corresponding amine. All methylxanthine hybrids were found to be AChE inhibitors, with some exhibiting potency comparable to that of tacrine. To assess the impact of these compounds on the nAChR, fluorescence spectroscopy and single-channel measurements were performed to evaluate their effects on the receptor's conformational state and functionality. Some of the compounds acted as partial agonists, although not all were capable of stabilizing the receptor in a desensitized state. To understand the molecular mechanisms underlying these results, we conducted molecular docking studies on both AChE and nAChR. The agonist activity of the synthesized caffeine analogs on the nAChR was found to depend on the accessory group, while the stabilization of the receptor in a desensitized state was associated with interactions involving the intermediate chain of the hybrid compounds at the binding site. Thus, we obtained a group of molecules that behave as cholinergic potentiators more efficiently than caffeine and also identified key features crucial for modulating the pharmacological targets under study.
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
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/11336/277771
Synthesis, biological evaluation and in silico analysis of new methylxanthine derivatives as potentiators of the cholinergic system.; LVI Reunión Anual de la Asociación Argentina de Farmacología Experimental; Bahía Blanca; Argentina; 2024; 51-51
978-631-90806-0-5
CONICET Digital
CONICET
url http://hdl.handle.net/11336/277771
identifier_str_mv Synthesis, biological evaluation and in silico analysis of new methylxanthine derivatives as potentiators of the cholinergic system.; LVI Reunión Anual de la Asociación Argentina de Farmacología Experimental; Bahía Blanca; Argentina; 2024; 51-51
978-631-90806-0-5
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://aafeargentina.org/congresos-aafe/
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
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application/pdf
application/pdf
dc.coverage.none.fl_str_mv Nacional
dc.publisher.none.fl_str_mv Asociación Argentina De Farmacología Experimental
publisher.none.fl_str_mv Asociación Argentina De Farmacología Experimental
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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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
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