The structure of the dopamine D3 receptor bound to cariprazine reveals principles for partial agonists with designed pharmacology
The third-generation antipsychotic cariprazine is a low-efficacy partial agonist of the dopamine D3 receptor (D3R). Here, we report the cryo–electron microscopy structure of cariprazine bound to D3R, establishing a framework for understanding ligand recognition in this receptor. We further determine structures of D3R in complex with a series of cariprazine derivatives spanning inverse agonists to high-efficacy partial agonists. Integration of structural data with pharmacological profiling and molecular dynamics simulations reveals how subtle chemical modifications translate into distinct functional outcomes. Determinants distinguishing agonism from inverse agonism are well defined, whereas differences among partial agonists arise from small positional shifts of the ligand within the orthosteric binding site. In contrast, the extended binding site primarily modulates ligand stability, affinity, and receptor selectivity. These findings establish a mechanistic link between bitopic ligand architecture and receptor activation, providing a “ligand-centric” view of D3R signaling. Leveraging these principles, we designed and validated cariprazine derivatives with enhanced D3/D2 selectivity and partial agonist activity. Together, this work provides a structural and pharmacological blueprint for the rational design of D3R-targeting ligands with tailored efficacy and therapeutic profiles.