D₂ Dopamine Receptor G Protein-Biased Partial Agonists Based on Cariprazine

Functionally selective G protein-coupled receptor ligands are valuable tools for deciphering the roles of downstream signaling pathways that potentially contribute to therapeutic effects versus side effects. Recently, we discovered both G_i/o-biased and β-arrestin2-biased D₂ receptor agonists based on the Food and Drug Administration (FDA)-approved drug aripiprazole. In this work, based on another FDA-approved drug, cariprazine, we conducted a structure-functional selectivity relationship study and discovered compound 38 (MS1768) as a potent partial agonist that selectively activates the G_i/o pathway over β-arrestin2. Unlike the dual D₂R/D₃R partial agonist cariprazine, compound 38 showed selective agonist activity for D₂R over D₃R. In fact, compound 38 exhibited potent antagonism of dopamine-stimulated β-arrestin2 recruitment. In our docking studies, compound 38 directly interacts with S193^5.42 on TM5 but has no interactions with extracellular loop 2, which appears to be in contrast to the binding poses of D₂R β-arrestin2-biased ligands. In in vivo studies, compound 38 showed high D₂R receptor occupancy in mice and effectively inhibited phencyclidine-induced hyperlocomotion.