2-(Fluoromethoxy)-4′-(S-methanesulfonimidoyl)-1,1′-biphenyl (UCM-1306), an Orally Bioavailable Positive Allosteric Modulator of the Human Dopamine D1 Receptor for Parkinson’s Disease

García Cárceles, Javier; Brea, José; Vázquez Villa, María Del Henar; Ladron de Guevara-Miranda, David; Cincilla, Giovanni; Sánchez Martínez, Melchor; Sánchez Merino, Anabel; Algar Lizana, Sergio; Teresa de los Frailes, María; Roberts, Richard S.; Ballesteros, Juan A.; Rodríguez De Fonseca, Fernando Antonio; Benhamú Salama, Bellinda; Loza, María I.; López Rodríguez, María Luz

2-(Fluoromethoxy)-4′-(S-methanesulfonimidoyl)-1,1′-biphenyl (UCM-1306), an Orally Bioavailable Positive Allosteric Modulator of the Human Dopamine D1 Receptor for Parkinson’s Disease

Tolerance development caused by dopamine replacement with L-DOPA and therapeutic drawbacks upon activation of dopaminergic receptors with orthosteric agonists reveal a significant unmet need for safe and effective treatment of Parkinson’s disease. In search for selective modulators of the D1 recepto...

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Autores:	García Cárceles, Javier, Brea, José, Vázquez Villa, María Del Henar, Ladron de Guevara-Miranda, David, Cincilla, Giovanni, Sánchez Martínez, Melchor, Sánchez Merino, Anabel, Algar Lizana, Sergio, Teresa de los Frailes, María, Roberts, Richard S., Ballesteros, Juan A., Rodríguez De Fonseca, Fernando Antonio, Benhamú Salama, Bellinda, Loza, María I., López Rodríguez, María Luz
Tipo de recurso:	artículo
Fecha de publicación:	2022
País:	España
Institución:	Universidad Complutense de Madrid (UCM)
Repositorio:	Docta Complutense
Idioma:	inglés
OAI Identifier:	oai:docta.ucm.es:20.500.14352/71989
Acceso en línea:	https://hdl.handle.net/20.500.14352/71989
Access Level:	acceso abierto
Palabra clave:	547 Química orgánica (Química) 2306 Química Orgánica

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spelling	2-(Fluoromethoxy)-4′-(S-methanesulfonimidoyl)-1,1′-biphenyl (UCM-1306), an Orally Bioavailable Positive Allosteric Modulator of the Human Dopamine D1 Receptor for Parkinson’s DiseaseGarcía Cárceles, JavierBrea, JoséVázquez Villa, María Del HenarLadron de Guevara-Miranda, DavidCincilla, GiovanniSánchez Martínez, MelchorSánchez Merino, AnabelAlgar Lizana, SergioTeresa de los Frailes, MaríaRoberts, Richard S.Ballesteros, Juan A.Rodríguez De Fonseca, Fernando AntonioBenhamú Salama, BellindaLoza, María I.López Rodríguez, María Luz547Química orgánica (Química)2306 Química OrgánicaTolerance development caused by dopamine replacement with L-DOPA and therapeutic drawbacks upon activation of dopaminergic receptors with orthosteric agonists reveal a significant unmet need for safe and effective treatment of Parkinson’s disease. In search for selective modulators of the D1 receptor, the screening of a chemical library and subsequent medicinal chemistry program around an identified hit resulted in new synthetic compound 26 [UCM-1306, 2-(fluoromethoxy)-4′- (S-methanesulfonimidoyl)-1,1′-biphenyl] that increases the dopamine maximal effect in a dose-dependent manner in human and mouse D1 receptors, is inactive in the absence of dopamine, modulates dopamine affinity for the receptor, exhibits subtype selectivity, and displays low binding competition with orthosteric ligands. The new allosteric modulator potentiates cocaine-induced locomotion and enhances L-DOPA recovery of decreased locomotor activity in reserpinized mice after oral administration. The behavior of compound 26 supports the interest of a positive allosteric modulator of the D1 receptor as a promising therapeutic approach for Parkinson’s disease.ACSUniversidad Complutense de Madrid20222022-08-3120222022-08-31journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/71989reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Atribución 3.0 Españahttps://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/719892026-06-02T12:44:21Z
dc.title.none.fl_str_mv	2-(Fluoromethoxy)-4′-(S-methanesulfonimidoyl)-1,1′-biphenyl (UCM-1306), an Orally Bioavailable Positive Allosteric Modulator of the Human Dopamine D1 Receptor for Parkinson’s Disease
title	2-(Fluoromethoxy)-4′-(S-methanesulfonimidoyl)-1,1′-biphenyl (UCM-1306), an Orally Bioavailable Positive Allosteric Modulator of the Human Dopamine D1 Receptor for Parkinson’s Disease
spellingShingle	2-(Fluoromethoxy)-4′-(S-methanesulfonimidoyl)-1,1′-biphenyl (UCM-1306), an Orally Bioavailable Positive Allosteric Modulator of the Human Dopamine D1 Receptor for Parkinson’s Disease García Cárceles, Javier 547 Química orgánica (Química) 2306 Química Orgánica
title_short	2-(Fluoromethoxy)-4′-(S-methanesulfonimidoyl)-1,1′-biphenyl (UCM-1306), an Orally Bioavailable Positive Allosteric Modulator of the Human Dopamine D1 Receptor for Parkinson’s Disease
title_full	2-(Fluoromethoxy)-4′-(S-methanesulfonimidoyl)-1,1′-biphenyl (UCM-1306), an Orally Bioavailable Positive Allosteric Modulator of the Human Dopamine D1 Receptor for Parkinson’s Disease
title_fullStr	2-(Fluoromethoxy)-4′-(S-methanesulfonimidoyl)-1,1′-biphenyl (UCM-1306), an Orally Bioavailable Positive Allosteric Modulator of the Human Dopamine D1 Receptor for Parkinson’s Disease
title_full_unstemmed	2-(Fluoromethoxy)-4′-(S-methanesulfonimidoyl)-1,1′-biphenyl (UCM-1306), an Orally Bioavailable Positive Allosteric Modulator of the Human Dopamine D1 Receptor for Parkinson’s Disease
title_sort	2-(Fluoromethoxy)-4′-(S-methanesulfonimidoyl)-1,1′-biphenyl (UCM-1306), an Orally Bioavailable Positive Allosteric Modulator of the Human Dopamine D1 Receptor for Parkinson’s Disease
dc.creator.none.fl_str_mv	García Cárceles, Javier Brea, José Vázquez Villa, María Del Henar Ladron de Guevara-Miranda, David Cincilla, Giovanni Sánchez Martínez, Melchor Sánchez Merino, Anabel Algar Lizana, Sergio Teresa de los Frailes, María Roberts, Richard S. Ballesteros, Juan A. Rodríguez De Fonseca, Fernando Antonio Benhamú Salama, Bellinda Loza, María I. López Rodríguez, María Luz
author	García Cárceles, Javier
author_facet	García Cárceles, Javier Brea, José Vázquez Villa, María Del Henar Ladron de Guevara-Miranda, David Cincilla, Giovanni Sánchez Martínez, Melchor Sánchez Merino, Anabel Algar Lizana, Sergio Teresa de los Frailes, María Roberts, Richard S. Ballesteros, Juan A. Rodríguez De Fonseca, Fernando Antonio Benhamú Salama, Bellinda Loza, María I. López Rodríguez, María Luz
author_role	author
author2	Brea, José Vázquez Villa, María Del Henar Ladron de Guevara-Miranda, David Cincilla, Giovanni Sánchez Martínez, Melchor Sánchez Merino, Anabel Algar Lizana, Sergio Teresa de los Frailes, María Roberts, Richard S. Ballesteros, Juan A. Rodríguez De Fonseca, Fernando Antonio Benhamú Salama, Bellinda Loza, María I. López Rodríguez, María Luz
author2_role	author author author author author author author author author author author author author author
dc.contributor.none.fl_str_mv	Universidad Complutense de Madrid
dc.subject.none.fl_str_mv	547 Química orgánica (Química) 2306 Química Orgánica
topic	547 Química orgánica (Química) 2306 Química Orgánica
description	Tolerance development caused by dopamine replacement with L-DOPA and therapeutic drawbacks upon activation of dopaminergic receptors with orthosteric agonists reveal a significant unmet need for safe and effective treatment of Parkinson’s disease. In search for selective modulators of the D1 receptor, the screening of a chemical library and subsequent medicinal chemistry program around an identified hit resulted in new synthetic compound 26 [UCM-1306, 2-(fluoromethoxy)-4′- (S-methanesulfonimidoyl)-1,1′-biphenyl] that increases the dopamine maximal effect in a dose-dependent manner in human and mouse D1 receptors, is inactive in the absence of dopamine, modulates dopamine affinity for the receptor, exhibits subtype selectivity, and displays low binding competition with orthosteric ligands. The new allosteric modulator potentiates cocaine-induced locomotion and enhances L-DOPA recovery of decreased locomotor activity in reserpinized mice after oral administration. The behavior of compound 26 supports the interest of a positive allosteric modulator of the D1 receptor as a promising therapeutic approach for Parkinson’s disease.
publishDate	2022
dc.date.none.fl_str_mv	2022 2022-08-31 2022 2022-08-31
dc.type.none.fl_str_mv	journal article http://purl.org/coar/resource_type/c_6501
dc.type.openaire.fl_str_mv	info:eu-repo/semantics/article
format	article
dc.identifier.none.fl_str_mv	https://hdl.handle.net/20.500.14352/71989
url	https://hdl.handle.net/20.500.14352/71989
dc.language.none.fl_str_mv	Inglés eng
language_invalid_str_mv	Inglés
language	eng
dc.rights.none.fl_str_mv	open access http://purl.org/coar/access_right/c_abf2 Atribución 3.0 España https://creativecommons.org/licenses/by/3.0/es/
dc.rights.openaire.fl_str_mv	info:eu-repo/semantics/openAccess
rights_invalid_str_mv	open access http://purl.org/coar/access_right/c_abf2 Atribución 3.0 España https://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf
dc.publisher.none.fl_str_mv	ACS
publisher.none.fl_str_mv	ACS
dc.source.none.fl_str_mv	reponame:Docta Complutense instname:Universidad Complutense de Madrid (UCM)
instname_str	Universidad Complutense de Madrid (UCM)
reponame_str	Docta Complutense
collection	Docta Complutense
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score	15,300719

2-(Fluoromethoxy)-4′-(S-methanesulfonimidoyl)-1,1′-biphenyl (UCM-1306), an Orally Bioavailable Positive Allosteric Modulator of the Human Dopamine D1 Receptor for Parkinson’s Disease

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