Department of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Drackendorfer Straße 1, D-07747 Jena, Germany.
Molecules. 2021 Jul 27;26(15):4509. doi: 10.3390/molecules26154509.
Opioid-associated overdoses and deaths due to respiratory depression are a major public health problem in the US and other Western countries. In the past decade, much research effort has been directed towards the development of G-protein-biased µ-opioid receptor (MOP) agonists as a possible means to circumvent this problem. The bias hypothesis proposes that G-protein signaling mediates analgesia, whereas ß-arrestin signaling mediates respiratory depression. SR-17018 was initially reported as a highly biased µ-opioid with an extremely wide therapeutic window. It was later shown that SR-17018 can also reverse morphine tolerance and prevent withdrawal via a hitherto unknown mechanism of action. Here, we examined the temporal dynamics of SR-17018-induced MOP phosphorylation and dephosphorylation. Exposure of MOP to saturating concentrations of SR-17018 for extended periods of time stimulated a MOP phosphorylation pattern that was indistinguishable from that induced by the full agonist DAMGO. Unlike DAMGO-induced MOP phosphorylation, which is reversible within minutes after agonist washout, SR-17018-induced MOP phosphorylation persisted for hours under otherwise identical conditions. Such delayed MOP dephosphorylation kinetics were also found for the partial agonist buprenorphine. However, buprenorphine, SR-17018-induced MOP phosphorylation was fully reversible when naloxone was included in the washout solution. SR-17018 exhibits a qualitative and temporal MOP phosphorylation profile that is strikingly different from any other known biased, partial, or full MOP agonist. We conclude that detailed analysis of receptor phosphorylation may provide novel insights into previously unappreciated pharmacological properties of newly synthesized MOP ligands.
阿片类药物相关的呼吸抑制导致的过量和死亡是美国和其他西方国家的一个主要公共卫生问题。在过去的十年中，大量的研究工作致力于开发 G 蛋白偏向性μ-阿片受体（MOP）激动剂，作为解决这个问题的一种可能方法。偏向假说提出，G 蛋白信号转导介导镇痛，而β-arrestin 信号转导介导呼吸抑制。SR-17018 最初被报道为一种高度偏向性的μ-阿片受体激动剂，具有极宽的治疗窗。后来发现，SR-17018 还可以通过一种迄今为止未知的作用机制逆转吗啡耐受和预防戒断。在这里，我们研究了 SR-17018 诱导的 MOP 磷酸化和去磷酸化的时间动态。将 MOP 暴露于饱和浓度的 SR-17018 中很长一段时间，会刺激一种与完全激动剂 DAMGO 诱导的 MOP 磷酸化模式无法区分的模式。与 DAMGO 诱导的 MOP 磷酸化不同，在激动剂洗脱后几分钟内，MOP 磷酸化是可逆的，而在相同条件下，SR-17018 诱导的 MOP 磷酸化持续数小时。部分激动剂丁丙诺啡也发现了类似的 MOP 去磷酸化动力学延迟。然而，当纳洛酮包含在洗脱溶液中时，SR-17018 诱导的 MOP 磷酸化是完全可逆的。SR-17018 表现出一种明显不同于任何其他已知的偏向性、部分性或完全性 MOP 激动剂的 MOP 磷酸化的定性和时间特性。我们得出结论，受体磷酸化的详细分析可能为新合成的 MOP 配体的以前未被重视的药理学特性提供新的见解。
