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

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