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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dc.contributor.authorGarcía Cárceles, Javier
dc.contributor.authorVázquez Villa, Henar
dc.contributor.authorBrea, José
dc.contributor.authorLadron de Guevara-Miranda, David
dc.contributor.authorCincilla, Giovanni
dc.contributor.authorSánchez Martínez, Melchor
dc.contributor.authorSánchez Merino, Anabel
dc.contributor.authorAlgar Lizana, Sergio
dc.contributor.authorTeresa de los Frailes, María
dc.contributor.authorRoberts, Richard S.
dc.contributor.authorBallesteros, Juan A.
dc.contributor.authorRodríguez de Fonseca, Fernando
dc.contributor.authorBenhamú Salama, Bellinda
dc.contributor.authorLoza, María I.
dc.contributor.authorLópez Rodríguez, María L.
dc.date.accessioned2023-06-22T10:59:55Z
dc.date.available2023-06-22T10:59:55Z
dc.date.issued2022-08-31
dc.descriptionCRUE-CSIC (Acuerdos Transformativos 2022)
dc.description.abstractTolerance 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.
dc.description.departmentDepto. de Química Orgánica
dc.description.facultyFac. de Ciencias Químicas
dc.description.refereedTRUE
dc.description.sponsorshipMinisterio de Ciencia e Innovación (MICINN)
dc.description.sponsorshipMinisterio de Ciencia e Innovación (MICINN)/FEDER
dc.description.sponsorshipInstituto de Salud Carlos III (ISCIII)/FEDER
dc.description.statuspub
dc.eprint.idhttps://eprints.ucm.es/id/eprint/74590
dc.identifier.doi10.1021/acs.jmedchem.2c00949
dc.identifier.issn0022-2623
dc.identifier.officialurlhttps://doi.org/10.1021/acs.jmedchem.2c00949
dc.identifier.urihttps://hdl.handle.net/20.500.14352/71989
dc.journal.titleJournal of Medicinal Chemistry
dc.language.isoeng
dc.publisherACS
dc.relation.projectIDPID2019-106279RB-I00
dc.relation.projectID(ERDF-EU, RD16/0017/0001)
dc.relation.projectIDISCIII and ERDF-EU (PI19/01577)
dc.rightsAtribución 3.0 España
dc.rights.accessRightsopen access
dc.rights.urihttps://creativecommons.org/licenses/by/3.0/es/
dc.subject.cdu547
dc.subject.ucmQuímica orgánica (Química)
dc.subject.unesco2306 Química Orgánica
dc.title2-(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.typejournal article
dspace.entity.typePublication
relation.isAuthorOfPublication86e2cdff-6568-4d8e-86a5-fc4a47e55dfd
relation.isAuthorOfPublication4e4d691c-4c40-4927-8569-2109d72ab618
relation.isAuthorOfPublication.latestForDiscovery86e2cdff-6568-4d8e-86a5-fc4a47e55dfd
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