2,3,9- and 2,3,11-Trisubstituted tetrahydroprotoberberines as D2 dopaminergic ligands

Autores
Párraga, Javier; Cabedo, Nuria; Andújar, Sebastián Antonio; Piqueras, Laura; Moreno, Laura; Galán, Abraham; Angelina, Emilio Luis; Enriz, Ricardo Daniel; Ivorra, María Dolores; Sanz, María Jesús; Cortes, Diego
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Dopamine-mediated neurotransmission plays an important role in relevant psychiatric and neurological disorders. Nowadays, there is an enormous interest in the development of new dopamine receptors (DR) acting drugs as potential new targets for the treatment of schizophrenia or Parkinson's disease. Previous studies have revealed that isoquinoline compounds such as tetrahydroisoquinolines (THIQs) and tetrahydroprotoberberines (THPBs) can behave as selective D2 dopaminergic alkaloids since they share structural similarities with dopamine. In the present study we have synthesized eleven 2,3,9- and 2,3,11-trisubstituted THPB compounds (six of them are described for the first time) and evaluated their potential dopaminergic activity. Binding studies on rat striatal membranes were used to evaluate their affinity and selectivity towards D1 and D2 DR and establish the structure–activity relationship (SAR) as dopaminergic agents. In general, all the tested THPBs with protected phenolic hydroxyls showed a lower affinity for D1 and D2 DR than their corresponding homologues with free hydroxyl groups. In previous studies in which dopaminergic affinity of 1-benzyl-THIQs (BTHIQs) was evaluated, the presence of a Cl into the A-ring resulted in increased affinity and selectivity towards D2 DR. This is in contrast with the current study since the existence of a chlorine atom into the A-ring of the THPBs caused increased affinity for D1 DR but dramatically reduced the selectivity for D2 DR. An OH group in position 9 of the THPB (9f) resulted in a higher affinity for DR than its homologue with an OH group in position 11 (9e) (250 fold for D2 DR). None of the compounds showed any cytotoxicity in freshly isolated human neutrophils. A molecular modelling study of three representative THPBs was carried out. The combination of MD simulations with DFT calculations provided a clear picture of the ligand binding interactions from a structural and energetic point of view. Therefore, it is likely that compound 9d (2,3,9-trihydroxy-THPB) behave as D2 DR agonist since serine residues cluster are crucial for agonist binding and receptor activation.
Fil: Párraga, Javier. Universidad de Valencia. Facultad de Farmacia. Departamento de Farmacología, Laboratorio de Farmacoquímica; España
Fil: Cabedo, Nuria. Universidad Politécnica de Valencia. Centro de Ecología Química Agrícola e Instituto Agroforestal Mediterráneo; España
Fil: Andújar, Sebastián Antonio. Universidad Nacional de San Luis; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Piqueras, Laura. Universidad de Valencia. Facultad de Medicina. Departamento de Farmacología; España
Fil: Moreno, Laura. Universidad de Valencia. Facultad de Farmacia. Departamento de Farmacología, Laboratorio de Farmacoquímica; España
Fil: Galán, Abraham. Universidad de Valencia. Facultad de Farmacia. Departamento de Farmacología, Laboratorio de Farmacoquímica; España
Fil: Angelina, Emilio Luis. Universidad Nacional de San Luis; Argentina
Fil: Enriz, Ricardo Daniel. Universidad Nacional de San Luis; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Ivorra, María Dolores. Universidad de Valencia. Facultad de Farmacia. Departamento de Farmacología, Laboratorio de Farmacoquímica; España
Fil: Sanz, María Jesús. Universidad de Valencia. Facultad de Medicina. Departamento de Farmacología; España. Instituto de Investigación Sanitaria; España
Fil: Cortes, Diego. Universidad de Valencia. Facultad de Farmacia. Departamento de Farmacología, Laboratorio de Farmacoquímica; España
Materia
Tetrahydroprotoberberines
Dopamine Receptors
Structureeactivity Relationships Cytotoxicity
Theoretical Calculations
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/4361
Acceder
id CONICETDig_13b65c10efe3d5682c5971c98d0b7d4a
oai_identifier_str oai:ri.conicet.gov.ar:11336/4361
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling 2,3,9- and 2,3,11-Trisubstituted tetrahydroprotoberberines as D2 dopaminergic ligandsPárraga, JavierCabedo, NuriaAndújar, Sebastián AntonioPiqueras, LauraMoreno, LauraGalán, AbrahamAngelina, Emilio LuisEnriz, Ricardo DanielIvorra, María DoloresSanz, María JesúsCortes, DiegoTetrahydroprotoberberinesDopamine ReceptorsStructureeactivity Relationships CytotoxicityTheoretical Calculationshttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Dopamine-mediated neurotransmission plays an important role in relevant psychiatric and neurological disorders. Nowadays, there is an enormous interest in the development of new dopamine receptors (DR) acting drugs as potential new targets for the treatment of schizophrenia or Parkinson's disease. Previous studies have revealed that isoquinoline compounds such as tetrahydroisoquinolines (THIQs) and tetrahydroprotoberberines (THPBs) can behave as selective D2 dopaminergic alkaloids since they share structural similarities with dopamine. In the present study we have synthesized eleven 2,3,9- and 2,3,11-trisubstituted THPB compounds (six of them are described for the first time) and evaluated their potential dopaminergic activity. Binding studies on rat striatal membranes were used to evaluate their affinity and selectivity towards D1 and D2 DR and establish the structure–activity relationship (SAR) as dopaminergic agents. In general, all the tested THPBs with protected phenolic hydroxyls showed a lower affinity for D1 and D2 DR than their corresponding homologues with free hydroxyl groups. In previous studies in which dopaminergic affinity of 1-benzyl-THIQs (BTHIQs) was evaluated, the presence of a Cl into the A-ring resulted in increased affinity and selectivity towards D2 DR. This is in contrast with the current study since the existence of a chlorine atom into the A-ring of the THPBs caused increased affinity for D1 DR but dramatically reduced the selectivity for D2 DR. An OH group in position 9 of the THPB (9f) resulted in a higher affinity for DR than its homologue with an OH group in position 11 (9e) (250 fold for D2 DR). None of the compounds showed any cytotoxicity in freshly isolated human neutrophils. A molecular modelling study of three representative THPBs was carried out. The combination of MD simulations with DFT calculations provided a clear picture of the ligand binding interactions from a structural and energetic point of view. Therefore, it is likely that compound 9d (2,3,9-trihydroxy-THPB) behave as D2 DR agonist since serine residues cluster are crucial for agonist binding and receptor activation.Fil: Párraga, Javier. Universidad de Valencia. Facultad de Farmacia. Departamento de Farmacología, Laboratorio de Farmacoquímica; EspañaFil: Cabedo, Nuria. Universidad Politécnica de Valencia. Centro de Ecología Química Agrícola e Instituto Agroforestal Mediterráneo; EspañaFil: Andújar, Sebastián Antonio. Universidad Nacional de San Luis; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Piqueras, Laura. Universidad de Valencia. Facultad de Medicina. Departamento de Farmacología; EspañaFil: Moreno, Laura. Universidad de Valencia. Facultad de Farmacia. Departamento de Farmacología, Laboratorio de Farmacoquímica; EspañaFil: Galán, Abraham. Universidad de Valencia. Facultad de Farmacia. Departamento de Farmacología, Laboratorio de Farmacoquímica; EspañaFil: Angelina, Emilio Luis. Universidad Nacional de San Luis; ArgentinaFil: Enriz, Ricardo Daniel. Universidad Nacional de San Luis; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Ivorra, María Dolores. Universidad de Valencia. Facultad de Farmacia. Departamento de Farmacología, Laboratorio de Farmacoquímica; EspañaFil: Sanz, María Jesús. Universidad de Valencia. Facultad de Medicina. Departamento de Farmacología; España. Instituto de Investigación Sanitaria; EspañaFil: Cortes, Diego. Universidad de Valencia. Facultad de Farmacia. Departamento de Farmacología, Laboratorio de Farmacoquímica; EspañaElsevier2013-08-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/4361Párraga, Javier; Cabedo, Nuria; Andújar, Sebastián Antonio; Piqueras, Laura; Moreno, Laura; et al.; 2,3,9- and 2,3,11-Trisubstituted tetrahydroprotoberberines as D2 dopaminergic ligands; Elsevier; European Journal of Medical Chemistry; 68; 11-8-2013; 150-1660223-5234enginfo:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0223523413004844info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ejmech.2013.07.036info:eu-repo/semantics/altIdentifier/issn/0223-5234info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T15:33:47Zoai:ri.conicet.gov.ar:11336/4361instacron: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:34982025-10-15 15:33:47.929CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv 2,3,9- and 2,3,11-Trisubstituted tetrahydroprotoberberines as D2 dopaminergic ligands
title 2,3,9- and 2,3,11-Trisubstituted tetrahydroprotoberberines as D2 dopaminergic ligands
spellingShingle 2,3,9- and 2,3,11-Trisubstituted tetrahydroprotoberberines as D2 dopaminergic ligands
Párraga, Javier
Tetrahydroprotoberberines
Dopamine Receptors
Structureeactivity Relationships Cytotoxicity
Theoretical Calculations
title_short 2,3,9- and 2,3,11-Trisubstituted tetrahydroprotoberberines as D2 dopaminergic ligands
title_full 2,3,9- and 2,3,11-Trisubstituted tetrahydroprotoberberines as D2 dopaminergic ligands
title_fullStr 2,3,9- and 2,3,11-Trisubstituted tetrahydroprotoberberines as D2 dopaminergic ligands
title_full_unstemmed 2,3,9- and 2,3,11-Trisubstituted tetrahydroprotoberberines as D2 dopaminergic ligands
title_sort 2,3,9- and 2,3,11-Trisubstituted tetrahydroprotoberberines as D2 dopaminergic ligands
dc.creator.none.fl_str_mv Párraga, Javier
Cabedo, Nuria
Andújar, Sebastián Antonio
Piqueras, Laura
Moreno, Laura
Galán, Abraham
Angelina, Emilio Luis
Enriz, Ricardo Daniel
Ivorra, María Dolores
Sanz, María Jesús
Cortes, Diego
author Párraga, Javier
author_facet Párraga, Javier
Cabedo, Nuria
Andújar, Sebastián Antonio
Piqueras, Laura
Moreno, Laura
Galán, Abraham
Angelina, Emilio Luis
Enriz, Ricardo Daniel
Ivorra, María Dolores
Sanz, María Jesús
Cortes, Diego
author_role author
author2 Cabedo, Nuria
Andújar, Sebastián Antonio
Piqueras, Laura
Moreno, Laura
Galán, Abraham
Angelina, Emilio Luis
Enriz, Ricardo Daniel
Ivorra, María Dolores
Sanz, María Jesús
Cortes, Diego
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Tetrahydroprotoberberines
Dopamine Receptors
Structureeactivity Relationships Cytotoxicity
Theoretical Calculations
topic Tetrahydroprotoberberines
Dopamine Receptors
Structureeactivity Relationships Cytotoxicity
Theoretical Calculations
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Dopamine-mediated neurotransmission plays an important role in relevant psychiatric and neurological disorders. Nowadays, there is an enormous interest in the development of new dopamine receptors (DR) acting drugs as potential new targets for the treatment of schizophrenia or Parkinson's disease. Previous studies have revealed that isoquinoline compounds such as tetrahydroisoquinolines (THIQs) and tetrahydroprotoberberines (THPBs) can behave as selective D2 dopaminergic alkaloids since they share structural similarities with dopamine. In the present study we have synthesized eleven 2,3,9- and 2,3,11-trisubstituted THPB compounds (six of them are described for the first time) and evaluated their potential dopaminergic activity. Binding studies on rat striatal membranes were used to evaluate their affinity and selectivity towards D1 and D2 DR and establish the structure–activity relationship (SAR) as dopaminergic agents. In general, all the tested THPBs with protected phenolic hydroxyls showed a lower affinity for D1 and D2 DR than their corresponding homologues with free hydroxyl groups. In previous studies in which dopaminergic affinity of 1-benzyl-THIQs (BTHIQs) was evaluated, the presence of a Cl into the A-ring resulted in increased affinity and selectivity towards D2 DR. This is in contrast with the current study since the existence of a chlorine atom into the A-ring of the THPBs caused increased affinity for D1 DR but dramatically reduced the selectivity for D2 DR. An OH group in position 9 of the THPB (9f) resulted in a higher affinity for DR than its homologue with an OH group in position 11 (9e) (250 fold for D2 DR). None of the compounds showed any cytotoxicity in freshly isolated human neutrophils. A molecular modelling study of three representative THPBs was carried out. The combination of MD simulations with DFT calculations provided a clear picture of the ligand binding interactions from a structural and energetic point of view. Therefore, it is likely that compound 9d (2,3,9-trihydroxy-THPB) behave as D2 DR agonist since serine residues cluster are crucial for agonist binding and receptor activation.
Fil: Párraga, Javier. Universidad de Valencia. Facultad de Farmacia. Departamento de Farmacología, Laboratorio de Farmacoquímica; España
Fil: Cabedo, Nuria. Universidad Politécnica de Valencia. Centro de Ecología Química Agrícola e Instituto Agroforestal Mediterráneo; España
Fil: Andújar, Sebastián Antonio. Universidad Nacional de San Luis; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Piqueras, Laura. Universidad de Valencia. Facultad de Medicina. Departamento de Farmacología; España
Fil: Moreno, Laura. Universidad de Valencia. Facultad de Farmacia. Departamento de Farmacología, Laboratorio de Farmacoquímica; España
Fil: Galán, Abraham. Universidad de Valencia. Facultad de Farmacia. Departamento de Farmacología, Laboratorio de Farmacoquímica; España
Fil: Angelina, Emilio Luis. Universidad Nacional de San Luis; Argentina
Fil: Enriz, Ricardo Daniel. Universidad Nacional de San Luis; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Ivorra, María Dolores. Universidad de Valencia. Facultad de Farmacia. Departamento de Farmacología, Laboratorio de Farmacoquímica; España
Fil: Sanz, María Jesús. Universidad de Valencia. Facultad de Medicina. Departamento de Farmacología; España. Instituto de Investigación Sanitaria; España
Fil: Cortes, Diego. Universidad de Valencia. Facultad de Farmacia. Departamento de Farmacología, Laboratorio de Farmacoquímica; España
description Dopamine-mediated neurotransmission plays an important role in relevant psychiatric and neurological disorders. Nowadays, there is an enormous interest in the development of new dopamine receptors (DR) acting drugs as potential new targets for the treatment of schizophrenia or Parkinson's disease. Previous studies have revealed that isoquinoline compounds such as tetrahydroisoquinolines (THIQs) and tetrahydroprotoberberines (THPBs) can behave as selective D2 dopaminergic alkaloids since they share structural similarities with dopamine. In the present study we have synthesized eleven 2,3,9- and 2,3,11-trisubstituted THPB compounds (six of them are described for the first time) and evaluated their potential dopaminergic activity. Binding studies on rat striatal membranes were used to evaluate their affinity and selectivity towards D1 and D2 DR and establish the structure–activity relationship (SAR) as dopaminergic agents. In general, all the tested THPBs with protected phenolic hydroxyls showed a lower affinity for D1 and D2 DR than their corresponding homologues with free hydroxyl groups. In previous studies in which dopaminergic affinity of 1-benzyl-THIQs (BTHIQs) was evaluated, the presence of a Cl into the A-ring resulted in increased affinity and selectivity towards D2 DR. This is in contrast with the current study since the existence of a chlorine atom into the A-ring of the THPBs caused increased affinity for D1 DR but dramatically reduced the selectivity for D2 DR. An OH group in position 9 of the THPB (9f) resulted in a higher affinity for DR than its homologue with an OH group in position 11 (9e) (250 fold for D2 DR). None of the compounds showed any cytotoxicity in freshly isolated human neutrophils. A molecular modelling study of three representative THPBs was carried out. The combination of MD simulations with DFT calculations provided a clear picture of the ligand binding interactions from a structural and energetic point of view. Therefore, it is likely that compound 9d (2,3,9-trihydroxy-THPB) behave as D2 DR agonist since serine residues cluster are crucial for agonist binding and receptor activation.
publishDate 2013
dc.date.none.fl_str_mv 2013-08-11
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/4361
Párraga, Javier; Cabedo, Nuria; Andújar, Sebastián Antonio; Piqueras, Laura; Moreno, Laura; et al.; 2,3,9- and 2,3,11-Trisubstituted tetrahydroprotoberberines as D2 dopaminergic ligands; Elsevier; European Journal of Medical Chemistry; 68; 11-8-2013; 150-166
0223-5234
url http://hdl.handle.net/11336/4361
identifier_str_mv Párraga, Javier; Cabedo, Nuria; Andújar, Sebastián Antonio; Piqueras, Laura; Moreno, Laura; et al.; 2,3,9- and 2,3,11-Trisubstituted tetrahydroprotoberberines as D2 dopaminergic ligands; Elsevier; European Journal of Medical Chemistry; 68; 11-8-2013; 150-166
0223-5234
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0223523413004844
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ejmech.2013.07.036
info:eu-repo/semantics/altIdentifier/issn/0223-5234
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
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_ 1846083467308171264
score 13.22299

Publicaciones similares