Dopamine D4 Receptor-Selective Compounds Reveal Structure-Activity Relationships that Engender Agonist Efficacy

Thomas M. Keck, R. Benjamin Free, Marilyn M. Day, Sonvia L. Brown, Michele S. Maddaluna, Griffin Fountain, Charles Cooper, Brooke Fallon, Matthew Holmes, Christopher T. Stang, Russell Burkhardt, Alessandro Bonifazi, Michael P. Ellenberger, Amy H. Newman, David R. Sibley, Chun Wu, Comfort A. Boateng

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

The dopamine D4 receptor (D4R) plays important roles in cognition, attention, and decision making. Novel D4R-selective ligands have promise in medication development for neuropsychiatric conditions, including Alzheimer's disease and substance use disorders. To identify new D4R-selective ligands, and to understand the molecular determinants of agonist efficacy at D4R, we report a series of eighteen novel ligands based on the classical D4R agonist A-412997 (1, 2-(4-(pyridin-2-yl)piperidin-1-yl)-N-(m-tolyl)acetamide). Compounds were profiled using radioligand binding displacement assays, β-arrestin recruitment assays, cyclic AMP inhibition assays, and molecular dynamics computational modeling. We identified several novel D4R-selective (Ki ≤ 4.3 nM and >100-fold vs other D2-like receptors) compounds with diverse partial agonist and antagonist profiles, falling into three structural groups. These compounds highlight receptor-ligand interactions that control efficacy at D2-like receptors and may provide insights into targeted drug discovery, leading to a better understanding of the role of D4Rs in neuropsychiatric disorders.

Original languageEnglish (US)
Pages (from-to)3722-3740
Number of pages19
JournalJournal of Medicinal Chemistry
Volume62
Issue number7
DOIs
StatePublished - Apr 11 2019

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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    Keck, T. M., Free, R. B., Day, M. M., Brown, S. L., Maddaluna, M. S., Fountain, G., Cooper, C., Fallon, B., Holmes, M., Stang, C. T., Burkhardt, R., Bonifazi, A., Ellenberger, M. P., Newman, A. H., Sibley, D. R., Wu, C., & Boateng, C. A. (2019). Dopamine D4 Receptor-Selective Compounds Reveal Structure-Activity Relationships that Engender Agonist Efficacy. Journal of Medicinal Chemistry, 62(7), 3722-3740. https://doi.org/10.1021/acs.jmedchem.9b00231