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 re...

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Detalles Bibliográficos
Autores: García-Cárceles, Javier, Vázquez-Villa, Henar, Brea, José, Ladron de Guevara-Miranda, David, Cincilla, Giovanni, Sánchez-Martínez, Melchor, Sánchez-Merino, Anabel, Algar, Sergio, Teresa de Los Frailes, María, Roberts, Richard S, Ballesteros, Juan A, Rodríguez de Fonseca, Fernando, Benhamú, Bellinda, Loza, María I, López-Rodríguez, María L
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/18754
Acceso en línea:http://hdl.handle.net/20.500.12105/18754
Access Level:acceso abierto
Palabra clave:Animals
Biphenyl Compounds
Cocaine
Dopamine
Dopamine Agents
Dopamine Agonists
Humans
Indazoles
Levodopa
Ligands
Mice
Nitrofurans
Parkinson Disease
Receptors, Dopamine
Receptors, Dopamine D1
Descripción
Sumario: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.

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