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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García Cárceles, Javier and Vázquez Villa, Henar and Brea, José and Ladron de Guevara-Miranda, David and Cincilla, Giovanni and Sánchez Martínez, Melchor and Sánchez Merino, Anabel and Algar Lizana, Sergio and Teresa de los Frailes, María and Roberts, Richard S. and Ballesteros, Juan A. and Rodríguez de Fonseca, Fernando and Benhamú Salama, Bellinda and Loza, María I. and López Rodríguez, María L. (2022) 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. Journal of Medicinal Chemistry . ISSN 0022-2623

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Official URL: https://doi.org/10.1021/acs.jmedchem.2c00949



Abstract

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.


Item Type:Article
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CRUE-CSIC (Acuerdos Transformativos 2022)

Subjects:Sciences > Chemistry > Chemistry, Organic
ID Code:74590
Deposited On:21 Sep 2022 10:23
Last Modified:21 Sep 2022 13:59

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