Biased agonism has been proposed as a means to separate desirable and adverse drug responses downstream of G protein-coupled receptor (GPCR) targets. Herein, we describe structural features of a series of mu-opioid-receptor (MOR)-selective agonists that preferentially activate receptors to couple to G proteins or to recruit βarrestin proteins. By comparing relative bias for MOR-mediated signaling in each pathway, we demonstrate a strong correlation between the respiratory suppression/antinociception therapeutic window in a series of compounds spanning a wide range of signaling bias. We find that βarrestin-biased compounds, such as fentanyl, are more likely to induce respiratory suppression at weak analgesic doses, while G protein signaling bias broadens the therapeutic window, allowing for antinociception in the absence of respiratory suppression.

中文翻译：

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偏倚因素和治疗窗口相关，可预测更安全的阿片类镇痛药。

提出了有偏激性激动作为在G蛋白偶联受体（GPCR）靶标下游分离所需药物反应和药物不良反应的手段。在这里，我们描述了一系列的μ阿片受体（MOR）选择性激动剂的结构特征，该激动剂优先激活受体以偶联至G蛋白或募集βarrestin蛋白。通过比较在每种途径中MOR介导的信号传导的相对偏倚，我们证明了一系列抑制信号传导偏倚的一系列化合物中的呼吸抑制/伤害感受治疗窗口之间存在很强的相关性。我们发现βarrestin偏倚的化合物（例如芬太尼）在较弱的镇痛剂量下更可能诱导呼吸抑制，而G蛋白信号偏向则扩大了治疗范围，从而在没有呼吸抑制的情况下具有镇痛作用。