Structure–Function Activity Relationships of Cariprazine Analogues with Distinct G Protein versus β-Arrestin Activities at the Dopamine D3 Receptor

Psychostimulant use disorder (PSUD) remains an unmet medical need, with no FDA-approved pharmacotherapies currently available. The dopamine D3 receptor (D₃R), due to its selective expression in mesolimbic reward circuits, has emerged as a compelling target for PSUD intervention. We used cariprazine (1a), a D₃R-preferring antipsychotic that reduces cocaine-related behaviors in preclinical models, as a scaffold for the synthesis of a library of novel derivatives. We employed BRET-based assays to functionally characterize their effects on G protein and β-arrestin2 signaling at D₃R. Structure–function relationship analyses revealed that modifications to the phenylpiperazine moiety of cariprazine are the key determinants of D₃R efficacy, potentially through diverse interactions with transmembrane segment 5. Moreover, certain substitutions to this aromatic primary pharmacophore appear to confer D₃R/D₂R functional divergence. These findings offer key mechanistic insights and inform the rational design of next-generation bitopic ligands with optimized signaling properties for the treatment of PSUD and related disorders.