Biased agonism at G protein–coupled receptors describes the phenomenon whereby some drugs can activate some downstream signaling activities to the relative exclusion of others. Descriptions of biased agonism focusing on the differential engagement of G proteins versus β-arrestins are commonly limited by the small response windows obtained in pathways that are not amplified or are less effectively coupled to receptor engagement, such as β-arrestin recruitment. At the μ-opioid receptor (MOR), G protein–biased ligands have been proposed to induce less constipation and respiratory depressant side effects than opioids commonly used to treat pain. However, it is unclear whether these improved safety profiles are due to a reduction in β-arrestin–mediated signaling or, alternatively, to their low intrinsic efficacy in all signaling pathways. Here, we systematically evaluated the most recent and promising MOR-biased ligands and assessed their pharmacological profile against existing opioid analgesics in assays not confounded by limited signal windows. We found that oliceridine, PZM21, and SR-17018 had low intrinsic efficacy. We also demonstrated a strong correlation between measures of efficacy for receptor activation, G protein coupling, and β-arrestin recruitment for all tested ligands. By measuring the antinociceptive and respiratory depressant effects of these ligands, we showed that the low intrinsic efficacy of opioid ligands can explain an improved side effect profile. Our results suggest a possible alternative mechanism underlying the improved therapeutic windows described for new opioid ligands, which should be taken into account for future descriptions of ligand action at this important therapeutic target.

G 蛋白偶联受体的偏向激动描述了一些药物可以激活一些下游信号活动而相对排斥其他药物的现象。偏向激动的描述侧重于 G 蛋白与 β-抑制蛋白的差异参与，通常受到在未放大或与受体参与不太有效耦合的途径中获得的小响应窗口的限制，例如 β-抑制蛋白募集。在 μ-阿片受体 (MOR) 上，与通常用于治疗疼痛的阿片类药物相比，偏向 G 蛋白的配体已被提议诱导更少的便秘和呼吸抑制副作用。然而，尚不清楚这些改善的安全性是由于 β-抑制蛋白介导的信号传导减少，还是由于它们在所有信号传导途径中的低内在功效。这里，我们系统地评估了最新的和有希望的 MOR 偏向配体，并在不受有限信号窗口混淆的分析中评估了它们对现有阿片类镇痛药的药理学特征。我们发现 oliceridine、PZM21 和 SR-17018 的内在功效较低。我们还证明了所有测试配体的受体激活、G 蛋白偶联和 β-抑制蛋白募集的功效测量之间的强相关性。通过测量这些配体的镇痛和呼吸抑制作用，我们表明阿片类配体的低内在功效可以解释改善的副作用。我们的结果表明，对于新的阿片类配体所描述的改进的治疗窗口可能存在替代机制，