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

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 (K_i ≤ 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.