Discovery, Characterization, and Optimization of a Novel Positive Allosteric Modulator-Antagonist of the D Dopamine Receptor.

To identify novel D3 dopamine receptor (D3R)-selective antagonist scaffolds, we conducted a high-throughput screen of a small-molecule library using a β-arrestin recruitment assay. The lead hit compound, , displayed unprecedented D3R selectivity as well as unusual positive allosteric modulator (PAM)-antagonist activity, which may confer unique therapeutic advantages to this scaffold. Iterative medicinal chemistry was used to synthesize and characterize 137 analogues, with several demonstrating both high D3R selectivity and improved D3R potency in β-arrestin recruitment and G protein activation assays. Two of the more promising analogues with 10-fold or greater improvements in potency, and , were further characterized and found to recapitulate both the allosteric PAM-antagonism and global D3R selectivity of . and also demonstrated favorable pharmacokinetics in mice suggesting that these compounds may serve as both research tools and therapeutic leads for the treatment of neuropsychiatric disorders, including substance use disorder.