Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D₃ Dopamine Receptor Agonist.

ABSTRACT: To identify novel D₃ dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selec

SUBMITTER: Moritz AE 

PROVIDER: S-EPMC7262777 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature