Biased signaling has emerged as an important concept in drug development targeting G protein-coupled receptors (GPCRs). Drugs that provoke biased signaling are expected to offer an opportunity for enhanced therapeutic effectiveness with minimized side effects. Opioid analgesics, while exerting potent pain-relieving effects, have become a social problem owing to their serious side effects. For the development of safer pain medications, there has been extensive exploration of agonists with a distinct balance of G-protein and β-arrestin (βarr) signaling. Recently, several approaches based on protein-protein interactions have been developed to precisely evaluate individual signal pathways, paving the way for the comprehensive analysis of biased signals. In this review, we describe an overview of bias signaling in opioid receptors, especially the μ-opioid receptor (MOR), and how to evaluate signaling bias in the GPCR field. We will also discuss future directions for rational drug development through the integration of diverse signal datasets.

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GPCR 信号偏差：阿片类药物开发的新兴框架

偏向信号传导已成为针对 G 蛋白偶联受体 (GPCR) 的药物开发中的一个重要概念。引发偏向信号传导的药物有望提供增强治疗效果并最大限度减少副作用的机会。阿片类镇痛药虽然具有有效的止痛作用，但由于其严重的副作用已成为一个社会问题。为了开发更安全的止痛药物，人们对具有 G 蛋白和 β-抑制蛋白 (βarr) 信号传导明显平衡的激动剂进行了广泛的探索。最近，已经开发了几种基于蛋白质-蛋白质相互作用的方法来精确评估个体信号通路，为偏差信号的综合分析铺平了道路。在这篇综述中，我们概述了阿片受体，特别是 μ-阿片受体 (MOR) 中的信号偏差，以及如何评估 GPCR 领域的信号偏差。我们还将通过整合不同的信号数据集来讨论合理药物开发的未来方向。