2026-08-05T09:54:40Zhttps://repisalud.isciii.es/rest/oai/request
oai:repisalud.isciii.es:20.500.12105/187542024-09-21T19:15:35Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16927
Repisalud author García-Cárceles, Javier author Vázquez-Villa, Henar author Brea, José author Ladron de Guevara-Miranda, David author Cincilla, Giovanni author Sánchez-Martínez, Melchor author Sánchez-Merino, Anabel author Algar, Sergio author Teresa de Los Frailes, María author Roberts, Richard S author Ballesteros, Juan A author Rodríguez de Fonseca, Fernando author Benhamú, Bellinda author Loza, María I author López-Rodríguez, María L 2024-02-27T15:10:31Z 2024-02-27T15:10:31Z 2022-08-31 10.1021/acs.jmedchem.2c00949 1520-4804 Journal of medicinal chemistry http://hdl.handle.net/10668/22592 36044544 http://hdl.handle.net/20.500.12105/18754 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. eng 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. research article