Dopamine D(4) Receptor-Selective Compounds Reveal Structure–Activity Relationships that Engender Agonist Efficacy

[Image: see text] The dopamine D(4) receptor (D(4)R) plays important roles in cognition, attention, and decision making. Novel D(4)R-selective ligands have promise in medication development for neuropsychiatric conditions, including Alzheimer’s disease and substance use disorders. To identify new D(4)R-selective ligands, and to understand the molecular determinants of agonist efficacy at D(4)R, we report a series of eighteen novel ligands based on the classical D(4)R 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 D(4)R-selective (K(i) ≤ 4.3 nM and >100-fold vs other D(2)-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 D(2)-like receptors and may provide insights into targeted drug discovery, leading to a better understanding of the role of D(4)Rs in neuropsychiatric disorders.