Natural Products as GPCR-Targeting Antidepressant Candidates: Advances and Opportunities.

Depression is a leading cause of disability worldwide, and currently available antidepressants are limited by delayed therapeutic onset, inadequate efficacy in some patients, and adverse effects. G protein-coupled receptors (GPCRs), the largest family of membrane receptors in the central nervous system, regulate neurotransmission, neuroplasticity, neuroinflammation, stress responses, and reward processing, and are therefore important targets for antidepressant drug development. Natural products are a rich source of structurally diverse bioactive compounds, many of which show antidepressant-like effects through the modulation of GPCR-mediated signaling pathways. In this narrative review, we summarize the roles of major GPCR families implicated in depression and provide an updated overview of natural products that modulate these receptors. We particularly emphasize receptor-specific mechanisms, downstream signaling networks, and the pharmacological actions of representative natural compounds. We also highlight emerging concepts in GPCR biology, including receptor heteromerization, signaling bias, and allosteric modulation, that may create new opportunities for antidepressant discovery. Finally, we discuss current challenges related to target validation, pharmacokinetics, and clinical translation. Collectively, these insights support further investigation of natural product-derived GPCR modulators as potential leads for next-generation antidepressant development.