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

Amy E. Moritz, R. Benjamin Free, Warren S. Weiner, Emmanuel O. Akano, Disha Gandhi, Ara Abramyan, Thomas M. Keck, Marc Ferrer, Xin Hu, Noel Southall, Joseph Steiner, Jeffrey Aubé, Lei Shi, Kevin J. Frankowski, David R. Sibley

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)5526-5567
Number of pages42
JournalJournal of Medicinal Chemistry
Volume63
Issue number10
DOIs
StatePublished - May 28 2020

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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