Biased Ligands of G Protein-Coupled Receptors (GPCRs): Structure–Functional Selectivity Relationships (SFSRs) and Therapeutic Potential

作者：Liang Tan, Wenzhong Yan, John D. McCorvy, Jianjun Cheng · 发表于：Journal of Medicinal Chemistry · 年份：2018 · DOI：10.1021/acs.jmedchem.8b00435 · 被引用次数：147 · 研究领域：Receptor Mechanisms and Signaling、Neuropeptides and Animal Physiology、Diabetes Treatment and Management

G protein-coupled receptors (GPCRs) signal through both G-protein-dependent and G-protein-independent pathways, and β-arrestin recruitment is the most recognized one of the latter. Biased ligands selective for either pathway are expected to regulate biological functions of GPCRs in a more precise way, therefore providing new drug molecules with superior efficacy and/or reduced side effects. During the past decade, biased ligands have been discovered and developed for many GPCRs, such as the μ opioid receptor, the angiotensin II receptor type 1, the dopamine D 2 receptor, and many others. In this Perspective, recent advances in this field are reviewed by discussing the structure–functional selectivity relationships (SFSRs) of GPCR biased ligands and the therapeutic potential of these molecules. Further understanding of the biological functions associated with each signaling pathway and structural basis for biased signaling will facilitate future drug design in this field.