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.