2. Academic Validation
  3. Discovery, Characterization, and Optimization of a Novel Positive Allosteric Modulator-Antagonist of the D3 Dopamine Receptor

Discovery, Characterization, and Optimization of a Novel Positive Allosteric Modulator-Antagonist of the D3 Dopamine Receptor

  • J Med Chem. 2025 Aug 14;68(15):16691-16749. doi: 10.1021/acs.jmedchem.5c01585.
Amy E Moritz 1,  Feijun Wang 2,  Nora S Madaras 1,  Amber M Kelley 2,  Kirsten K Snyder 1,  Disha Gandhi 2,  Laura R Inbody 1,  Emmanuel O Akano 1,  Lei Shi 3,  J Robert Lane 4 5,  R Benjamin Free 1,  Kevin J Frankowski 2,  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 Center for Integrative Chemical Biology and Drug Discovery, UNC Eshelman School of Pharmacy, 125 Mason Farm Road, Chapel Hill, North Carolina 27599, United States.
  • 3 Computational Chemistry and Molecular Biophysics Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, United States.
  • 4 Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, U.K.
  • 5 Centre of Membrane Proteins and Receptors, University of Birmingham and University of Nottingham, Nottingham NG7 2UH, U.K.
PMID: 40748686 DOI: 10.1021/acs.jmedchem.5c01585
Abstract

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, MLS6357, 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, 6a and 10aa, were further characterized and found to recapitulate both the allosteric PAM-antagonism and global D3R selectivity of MLS6357. 6a and 10aa 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.

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