RT Journal Article
T1 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
A1 García Cárceles, Javier
A1 Brea, José
A1 Vázquez Villa, María Del Henar
A1 Ladron de Guevara-Miranda, David
A1 Cincilla, Giovanni
A1 Sánchez Martínez, Melchor
A1 Sánchez Merino, Anabel
A1 Algar Lizana, Sergio
A1 Teresa de los Frailes, María
A1 Roberts, Richard S.
A1 Ballesteros, Juan A.
A1 Rodríguez De Fonseca, Fernando Antonio
A1 Benhamú Salama, Bellinda
A1 Loza, María I.
A1 López Rodríguez, María Luz
AB 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.
PB ACS
SN 0022-2623
YR 2022
FD 2022-08-31
LK https://hdl.handle.net/20.500.14352/71989
UL https://hdl.handle.net/20.500.14352/71989
LA eng
NO CRUE-CSIC (Acuerdos Transformativos 2022)
NO Ministerio de Ciencia e Innovación (MICINN)
NO Ministerio de Ciencia e Innovación (MICINN)/FEDER
NO Instituto de Salud Carlos III (ISCIII)/FEDER
DS Docta Complutense
RD 10 abr 2025