Therapeutic exploration of biased ligands at class A G protein-coupled receptors over the past 20 years

Recent decades have witnessed significant advances in the development of biased ligands for G protein-coupled receptors (GPCRs) as potential therapeutic agents with enhanced efficacy and reduced on-target side effects. This is largely attributed to the unique capability of biased ligands to activate pathway-selective signaling, which can effectively modulate in vivo pharmacology. This review presents a comprehensive analysis of biased ligands targeting class A GPCRs over the past 20 years, encompassing discovery strategies, assays, biological effects and therapeutic applications. The analysis covers approximately 383 biased ligands acting on 60 different GPCRs, among which opioid, 5-hydroxytryptamine, dopamine, adrenergic and cannabinoid receptors are the five subfamilies with the highest number of reported biased ligands. The biological effects of these biased ligands are primarily investigated in the area of pain, cardiovascular, neurological, respiratory, metabolic and inflammatory diseases. The regulatory approval of the opioid biased agonist TRV130 for pain management, along with the growing number of biased drugs tested in clinical trials, heralds a new era in GPCR drug development. Additionally, various natural product biased ligands have been identified. A deeper understanding of the biological functions and pharmacological effects of biased ligands will support future advancements in GPCR drug development.