García 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 Luz2023-06-222023-06-222022-08-310022-262310.1021/acs.jmedchem.2c00949https://hdl.handle.net/20.500.14352/71989CRUE-CSIC (Acuerdos Transformativos 2022)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.engAtribución 3.0 Españahttps://creativecommons.org/licenses/by/3.0/es/journal articlehttps://doi.org/10.1021/acs.jmedchem.2c00949open access547Química orgánica (Química)2306 Química Orgánica