FDA Drug Repurposing Uncovers Modulators of Dopamine D2 Receptor Localization via Disruption of the NCS‑1 Interaction

Dopamine D2 receptor (D2R) regulates key aspects of motor control, cognition, and reward. Its function depends not only on ligand binding and signaling efficacy but also on the dynamic control of receptor localization at the cell surface. Neuronal calcium sensor 1 (NCS-1) interacts with D2R in a Ca2+-dependent manner. Using in vitro and cellular assays, we found that NCS-1 promotes D2R trafficking to the plasma membrane through active exocytosis while preserving canonical receptor pharmacology. A screen of FDA-approved drugs identified protein–protein interaction (PPI) modulators targeting the NCS-1/D2R interface. Azilsartan medoxomil, atorvastatin, and vilazodone disrupt this interaction, reducing D2R surface expression. Structural studies revealed that these compounds target NCS-1, overlap the D2R binding site, and perturb the dynamics of the regulatory helix H10. These findings reveal an unexploited intracellular mechanism to modulate D2R function via PPI modulation, offering a novel strategy to fine-tune dopaminergic tone beyond receptor blockade or direct agonism.