Precision pharmacology of CNS GPCRs: From biased signaling to translational therapeutics

G protein-coupled receptors (GPCRs) represent one of the most extensively targeted receptor families in central nervous system (CNS) pharmacology. Recent advances in GPCR biology have transformed traditional paradigms by introducing concepts such as biased signaling, allosteric modulation, and compartmentalized receptor trafficking, enabling pathway-specific therapeutic interventions. These developments have been further accelerated by emerging technologies, including high-resolution cryo-electron microscopy, biosensor platforms (e.g., BRET/FRET), human iPSC-derived models, and computational approaches such as molecular dynamics and artificial intelligence-driven drug discovery. This review provides a comprehensive overview of the evolving landscape of CNS GPCR pharmacology, integrating mechanistic insights with translational applications. Key receptor systems, including dopamine, serotonin, opioid, trace amine-associated receptor 1 (TAAR1), and GPR139, are discussed in the context of current and emerging therapeutics. In addition, advances in Class C GPCRs, including metabotropic glutamate and GABA-B receptors, are highlighted. Despite significant progress, challenges such as blood-brain barrier permeability, limited predictive biomarkers, and high attrition rates in clinical trials continue to hinder successful drug development. The convergence of receptor pharmacology, translational technologies, and precision medicine approaches offers a promising framework for overcoming these limitations. Overall, next-generation GPCR-targeted strategies hold substantial potential for developing safe, effective, and individualized therapies for CNS disorders.