Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists
Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists
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DOI：
10.1126/scisignal.aaz3140
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发表时间：
2020-03-31
影响因子：
7.3
通讯作者：
Canals, Meritxell
中科院分区：
文献类型：
--
作者：
Gillis, Alexander;Gondin, Arisbel B.;Canals, Meritxell
在G蛋白偶联受体上的偏向激动作用描述了这样的现象，即一些药物可以激活一些下游信号传导活性而相对排斥其他活性。侧重于G蛋白与β-抑制蛋白差异接合的偏倚激动作用的描述通常受到在未扩增或与受体接合偶联效率较低的途径（如β-抑制蛋白募集）中获得的小响应窗口的限制。在β-阿片受体（莫尔）处，已经提出G蛋白偏向性配体比通常用于治疗疼痛的阿片类药物诱导更少的便秘和呼吸道阻塞副作用。然而，目前尚不清楚这些改善的安全性特征是由于β-抑制蛋白介导的信号传导减少，还是由于其在所有信号传导途径中的内在疗效较低。在这里，我们系统地评估了最新的和有前途的MOR偏置配体，并评估了其药理学特性对现有的阿片类镇痛药的测定不混淆有限的信号窗口。我们发现，oliceridine，PZM 21和SR-17018具有较低的内在疗效。我们还证明了所有测试配体的受体活化、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抗伤害感受和呼吸抑制作用，我们表明阿片样物质配体的低内在功效可以解释改善的副作用概况。我们的研究结果表明，一个可能的替代机制的基础上改进的治疗窗口描述新的阿片类配体，这应该考虑到未来的描述配体作用在这个重要的治疗目标。
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 beta-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 beta-arrestin recruitment. At the beta-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 beta-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 beta-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.