GPCR heteromers: Beyond the monomeric paradigm in neuropsychiatric drug discovery

G protein-coupled receptors (GPCRs) constitute the largest druggable superfamily of membrane proteins and underlie approximately 35% of all approved medicines. Yet this conventional paradigm leaves a substantial minority of neuropsychiatric patients with incomplete efficacy, treatment resistance, or dose-limiting adverse effects. Converging evidence from structural biology, single-molecule biophysics, and molecular pharmacology has dismantled the monomeric model. GPCRs function in vivo as dynamic homomeric and heteromeric complexes in brain regions directly implicated in disease, including the striatum, prefrontal cortex, hippocampus, and extended amygdala. Here, we advance the central proposition that the effective drug target in the central nervous system is not an isolated receptor monomer but a context-dependent macromolecular assembly whose ligand-binding, signaling, and trafficking properties arise from specific protein-protein interactions. We synthesize evidence for exemplary heteromers across disease-relevant circuits, A2AR-D2R in the striatum, 5-HT2AR-mGlu2R in the prefrontal cortex, D1R-D2R and D1R-mGlu5R in the striatum, D2R-5-HT2AR, and higher-order A2AR-D2R-mGlu5R assemblies together with Sigma-1 receptor-mediated modulation. We then assess translational strategies, including bitopic ligands, nanobodies, and cryo-EM-guided structure-based design, and propose a roadmap centered on native-tissue validation, state-selective assays, and circuit-level behavioral readouts. This perspective provides a conceptual framework for achieving anatomical selectivity, signaling precision, and the uncoupling of therapeutic efficacy from adverse effects.