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 (SUD). To identify new D4R-selective ligands, and to understand the molecular determinants of agonist efficacy at D4R, we report a series of eighteen ligands based on the classical D4R agonist A-412997 (2-(4-(pyridin-2-yl)piperidin-1-yl)-N-(m-tolyl)acetamide). Compounds were profiled using radioligand binding displacement assays, β-arrestin recruitment assays, cAMP inhibition assays, and molecular dynamic computational modeling. We identified several novel D4R-selective (Ki ≤ 4.3 nM and &gt;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 to targeted drug discovery leading to a better understanding of the role of D4Rs in neuropsychiatric disorders.

D4R-Selective compounds reveal structure-activity relationships that engender agonist efficacy

2019 Fall National Meeting

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