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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Authors: García-Cárceles, Javier, Vázquez-Villa, Henar, Brea Floriani, José Manuel, Ladron de Guevara-Miranda, David, Cincilla, Giovanni, Sánchez-Martínez, Melchor, Sánchez-Merino, Anabel, Algar, Sergio, Frailes, María Teresa de los, Roberts, Richard S., Ballesteros, Juan A., Rodríguez de Fonseca, Fernando, Benhamú, Bellinda, Loza García, María Isabel, López-Rodríguez, María L.
Format: article
Publication Date:2022
Country:España
Institution:Universidad de Santiago de Compostela (USC)
Repository:Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela
Language:English
OAI Identifier:oai:minerva.usc.gal:10347/45418
Online Access:https://hdl.handle.net/10347/45418
Access Level:Open access
Keyword:3209 Farmacología
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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, JavierVázquez-Villa, HenarBrea Floriani, José ManuelLadron de Guevara-Miranda, DavidCincilla, GiovanniSánchez-Martínez, MelchorSánchez-Merino, AnabelAlgar, SergioFrailes, María Teresa de losRoberts, Richard S.Ballesteros, Juan A.Rodríguez de Fonseca, FernandoBenhamú, BellindaLoza García, María IsabelLópez-Rodríguez, María L.3209 FarmacologíaTolerance 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.ACS PublicationsUniversidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS)Universidade de Santiago de Compostela. Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica20222022-08-3120222022-08-31journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10347/45418reponame:Minerva. Repositorio Institucional de la Universidad de Santiago de Compostelainstname:Universidad de Santiago de Compostela (USC)InglésengAgencia Estatal de Investigación http://dx.doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 AEI ESEC ERDF RD16%2F0017%2F0001EC ERDF PI19%2F01577open accesshttp://purl.org/coar/access_right/c_abf2© 2022 The Authors. Published by American Chemical Societyhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:minerva.usc.gal:10347/454182026-06-15T12:47:27Z
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
3209 Farmacología
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
Vázquez-Villa, Henar
Brea Floriani, José Manuel
Ladron de Guevara-Miranda, David
Cincilla, Giovanni
Sánchez-Martínez, Melchor
Sánchez-Merino, Anabel
Algar, Sergio
Frailes, María Teresa de los
Roberts, Richard S.
Ballesteros, Juan A.
Rodríguez de Fonseca, Fernando
Benhamú, Bellinda
Loza García, María Isabel
López-Rodríguez, María L.
author García-Cárceles, Javier
author_facet García-Cárceles, Javier
Vázquez-Villa, Henar
Brea Floriani, José Manuel
Ladron de Guevara-Miranda, David
Cincilla, Giovanni
Sánchez-Martínez, Melchor
Sánchez-Merino, Anabel
Algar, Sergio
Frailes, María Teresa de los
Roberts, Richard S.
Ballesteros, Juan A.
Rodríguez de Fonseca, Fernando
Benhamú, Bellinda
Loza García, María Isabel
López-Rodríguez, María L.
author_role author
author2 Vázquez-Villa, Henar
Brea Floriani, José Manuel
Ladron de Guevara-Miranda, David
Cincilla, Giovanni
Sánchez-Martínez, Melchor
Sánchez-Merino, Anabel
Algar, Sergio
Frailes, María Teresa de los
Roberts, Richard S.
Ballesteros, Juan A.
Rodríguez de Fonseca, Fernando
Benhamú, Bellinda
Loza García, María Isabel
López-Rodríguez, María L.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS)
Universidade de Santiago de Compostela. Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica
dc.subject.none.fl_str_mv 3209 Farmacología
topic 3209 Farmacología
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
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/10347/45418
url https://hdl.handle.net/10347/45418
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Agencia Estatal de Investigación http://dx.doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 AEI ES
EC ERDF RD16%2F0017%2F0001
EC ERDF PI19%2F01577
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
© 2022 The Authors. Published by American Chemical Society
http://creativecommons.org/licenses/by/4.0/
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
© 2022 The Authors. Published by American Chemical Society
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv ACS Publications
publisher.none.fl_str_mv ACS Publications
dc.source.none.fl_str_mv reponame:Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela
instname:Universidad de Santiago de Compostela (USC)
instname_str Universidad de Santiago de Compostela (USC)
reponame_str Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela
collection Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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