Low Intrinsic Efficacy Alone Cannot Explain the Improved Side Effect Profiles of New Opioid Agonists

In a recent report in Science Signaling (Gillis, A., et al. Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists. Sci. Signaling2020, 13, eaaz314010.1126/scisignal.aaz3140), it was suggested that low intrinsic agonism, and not biased agonism, leads to an improvement in the separation of potency in opioid-induced respiratory suppression versus antinociception. Although many of the compounds that were tested have been shown to display G protein signaling bias in prior publications, the authors conclude that because they cannot detect biased agonism in their cellular signaling studies the compounds are therefore not biased agonists. Rather, they conclude that it is low intrinsic efficacy that leads to the therapeutic window improvement. Intrinsic efficacy is the extent to which an agonist can stimulate a G protein-coupled receptor response in a system, while biased agonism takes into consideration not only the intrinsic efficacy but also the potency of an agonist in an assay. Herein, we have reanalyzed the data presented in the published work (10.1126/scisignal.aaz3140) [including the recent Erratum (10.1126/scisignal.abf9803)] to derive intrinsic efficacy and bias factors as ΔΔlog(τ/KA) and ΔΔlog(Emax/EC50), respectively. On the basis of this reanalysis, the data support the conclusion that biased agonism, favoring G protein signaling, was observed. Moreover, a conservation of rank order intrinsic efficacy was not observed upon comparing responses in each assay, further suggesting that multiple active receptor states were present. These observations agree with prior studies in which oliceridine, PZM21, and SR-17018 were first described as biased agonists with improvement in antinociception over respiratory suppression in mice. Therefore, the data in the Science Signaling paper provide strong corroborating evidence that G protein signaling bias may be a means of improving opioid analgesia while avoiding certain undesirable side effects.发表于《科学·信号传导》（Science Signaling）的一项近期研究（Gillis, A. 等. G蛋白激活的低内在活性可解释新型阿片类激动剂的优化副作用谱. Sci. Signaling 2020, 13, eaaz314010.1126/scisignal.aaz3140）提出，是低内在激动活性而非偏倚激动（biased agonism），改善了阿片类药物诱导的呼吸抑制与抗伤害感受之间的效力分离度。尽管此前已有多篇文献证实，本次研究测试的多种化合物均表现出G蛋白信号通路（G protein signaling）偏倚，但作者却得出结论：由于在细胞信号传导研究中未检测到偏倚激动现象，因此这些化合物并非偏倚激动剂。相反，他们认为是低内在活性（intrinsic efficacy）促成了治疗窗口的优化。内在活性指的是在某一系统中，激动剂刺激G蛋白偶联受体（G protein-coupled receptor）产生应答的能力上限；而偏倚激动则不仅考虑内在活性，还包含激动剂在某一检测实验中的效力。本研究对该已发表研究（10.1126/scisignal.aaz3140）[含后续更正勘误（10.1126/scisignal.abf9803）]的数据进行了重新分析，分别以ΔΔlog(τ/KA)和ΔΔlog(Emax/EC50)作为内在活性与偏倚因子的计算参数。基于本次重新分析的结果，数据支持如下结论：研究中观察到了偏向G蛋白信号通路的偏倚激动现象。此外，在对比不同检测实验的应答结果时，并未观察到内在活性的排序守恒，这进一步提示存在多种活性受体状态。上述观测结果与既往研究一致——奥利替丁（oliceridine）、PZM21及SR-17018最初即被描述为偏倚激动剂，在小鼠模型中可实现抗伤害感受作用优于呼吸抑制。因此，《科学·信号传导》刊载的该研究数据，为“G蛋白信号通路偏倚可作为优化阿片类镇痛效果、规避部分不良副作用的手段”这一观点提供了强有力的佐证。