Therapeutic targeting of G protein-coupled receptors in central nervous system disorders: from novel mechanisms to precision pharmacology.

G protein-coupled receptors (GPCRs) are major therapeutic targets for central nervous system disorders, with more than 500 approved drugs targeting this receptor family worldwide. This review comprehensively examines the pathophysiological roles and therapeutic potential of GPCRs in major neurological and psychiatric disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), and depression. We highlight how dysregulated signaling through specific GPCRs, including dopamine and adenosine A2A receptors in PD, the mGlu5 receptor and muscarinic acetylcholine receptors in AD, S1P and GPR17 receptors in MS, and 5-HT1A and GPR39 receptors in depression, contributes to disease pathogenesis. Beyond canonical monomeric activation, this review emphasizes emerging concepts in GPCR heterodimerization (e.g., the 5-HT1A/orexin 1 receptor complex activating Gαs pathways), biased signaling, and allosteric modulation, which provide opportunities to develop therapeutics with greater specificity and fewer adverse effects. We also evaluate the therapeutic potential of targeting these mechanisms using specific pharmacological agents, including synthetic compounds and structurally defined natural product-derived molecules. The chemical structures of key natural products-including paeoniflorin, rosmarinic acid, and ergothioneine-are presented, with their GPCR interactions and critical pharmacophores highlighted. Finally, we discuss future directions involving advanced technologies, including cryo-electron microscopy, induced pluripotent stem cell-derived brain organoids, structural biology, and artificial intelligence, to improve understanding of complex GPCR signaling. The development of biased ligands, stage-specific interventions, and GPCR-based biomarkers represents a critical step toward personalized and more effective treatments for neurological disorders.