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

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

  • J Med Chem. 2020 May 28;63(10):5526-5567. doi: 10.1021/acs.jmedchem.0c00424.
Amy E Moritz 1,  R Benjamin Free 1,  Warren S Weiner 2,  Emmanuel O Akano 1,  Disha Gandhi 3,  Ara Abramyan 4,  Thomas M Keck 5,  Marc Ferrer 6,  Xin Hu 6,  Noel Southall 6,  Joseph Steiner 7,  Jeffrey Aubé 2 3,  Lei Shi 4,  Kevin J Frankowski 2 3,  David R Sibley 1
Affiliations

Affiliations

  • 1 Molecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke, Intramural Research Program, National Institutes of Health, 35 Convent Drive, MSC-3723, Bethesda, Maryland 20892-3723, United States.
  • 2 University of Kansas Specialized Chemistry Center, University of Kansas, Lawrence, Kansas 66047, United States.
  • 3 Center for Integrative Chemical Biology and Drug Discovery, UNC Eshelman School of Pharmacy, 125 Mason Farm Road, Chapel Hill, North Carolina 27599, United States.
  • 4 Computational Chemistry and Molecular Biophysics Unit, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Maryland, 333 Cassell Drive, Baltimore, Maryland 21224, United States.
  • 5 Department of Chemistry & Biochemistry, Department of Molecular & Cellular Biosciences, College of Science and Mathematics, Rowan University, 201 Mullica Hill Road, Glassboro, New Jersey 08028, United States.
  • 6 NIH Chemical Genomics Center, Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
  • 7 NeuroTherapeutics Development Unit, National Institute for Neurological Disorders and Stroke, Intramural Research Program, National Institutes of Health, Bethesda, Maryland 20892, United States.
PMID: 32342685 DOI: 10.1021/acs.jmedchem.0c00424
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.

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