The dopamine D4 receptor (D4R) is enriched in the prefrontal cortex where it plays important roles in cognition, attention, decision making and executive function. 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 novel 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 >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 such as SUD.

Learning Objectives:

1.  Identify various challenges in designing medication in treating Substance Use Disorders

2.  Understanding the role of dopamine receptors in developing therapies for the treatment of  Substance Use Disorders

3. Understanding of receptor-ligand interactions that control efficacy.