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 D-1 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 D-1 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 D-1 receptor as a promising therapeutic approach for Parkinson's disease.

Automated summary

The development of tolerance caused by dopamine replacement and therapeutic drawbacks of dopaminergic receptors activation highlight the urgent need for a safe and effective treatment for Parkinson's disease. Compound 26, a new synthetic compound designed as a selective modulator of D-1 receptor, demonstrates dose-dependent increase in dopamine's maximal effect in human and mouse D-1 receptors, while being inactive in the absence of dopamine. It shows subtype selectivity and low binding competition with orthosteric ligands. Compound 26 enhances cocaine-induced locomotion and L-DOPA recovery of locomotor activity in reserpinized mice, suggesting its potential as a positive allosteric modulator for Parkinson's disease.