Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D-3 Dopamine Receptor Agonist

• Published in: Journal of medicinal chemistry Vol. 63; no. 10; pp. 5526 - 5567
• Main Authors: Moritz, Amy E., Free, R. Benjamin, Weiner, Warren S., Akano, Emmanuel O., Gandhi, Disha, Abramyan, Ara, Keck, Thomas M., Ferrer, Marc, Hu, Xin, Southall, Noel, Steiner, Joseph, Aube, Jeffrey, Shi, Lei, Frankowski, Kevin J., Sibley, David R.
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 28.05.2020
• Subjects: Animals; Chemistry, Medicinal; CHO Cells; Cricetulus; Dopamine Agonists - chemistry; Dopamine Agonists - metabolism; Dopamine Agonists - pharmacology; Dose-Response Relationship, Drug; Drug Discovery - methods; HEK293 Cells; Hep G2 Cells; Humans; Induced Pluripotent Stem Cells - drug effects; Induced Pluripotent Stem Cells - metabolism; Life Sciences & Biomedicine; Male; Mice; Mice, Inbred C57BL; Pharmacology & Pharmacy; Protein Structure, Secondary; Receptors, Dopamine D3 - agonists; Receptors, Dopamine D3 - chemistry; Receptors, Dopamine D3 - metabolism; Science & Technology; POTENT; IMPULSE CONTROL DISORDERS; CRYSTAL-STRUCTURE; BIVALENT LIGANDS; IN-VIVO; HIGH-AFFINITY; PRAMIPEXOLE; FORCE-FIELD; D3 RECEPTOR; MPTP TOXICITY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c00424

To identify novel D-3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a beta-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 beta-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 selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.