School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
Int J Mol Sci. 2020 Jul 1;21(13):4699. doi: 10.3390/ijms21134699.
Opioid analgesics such as morphine have indispensable roles in analgesia. However, morphine use can elicit side effects such as respiratory depression and constipation. It has been reported that G protein-biased agonists as substitutes for classic opioid agonists can alleviate (or even eliminate) these side effects. The compounds PZM21 and TRV130 could be such alternatives. Nevertheless, there are controversies regarding the efficacy and G protein-biased ability of PZM21. To demonstrate a rationale for the reduced biasing agonism of PZM21 compared with that of TRV130 at the molecular level, we undertook a long-term molecular dynamics simulation of the μ-opioid receptor (MOR) upon the binding of three ligands: morphine, TRV130, and PZM21. We found that the delayed movement of the W293 (Ballesteros-Weinstein numbering) side chain was a factor determining the dose-dependent agonism of PZM21. Differences in conformational changes of W318, Y326, and Y336 in PZM21 and TRV130 explained the observed differences in bias between these ligands. The extent of water movements across the receptor channel was correlated with analgesic effects. Taken together, these data suggest that the observed differences in conformational changes of the studied MOR-ligand complexes point to the low-potency and lower bias effects of PZM21 compared with the other two ligands, and they lay the foundation for the development of G protein-biased agonists.
阿片类镇痛药如吗啡在镇痛中具有不可或缺的作用。然而，吗啡的使用会引起副作用，如呼吸抑制和便秘。据报道，G 蛋白偏向激动剂可以替代经典的阿片类激动剂，从而减轻（甚至消除）这些副作用。化合物 PZM21 和 TRV130 可能就是这样的替代品。然而，关于 PZM21 的疗效和 G 蛋白偏向能力仍存在争议。为了从分子水平上证明 PZM21 与 TRV130 相比，其偏向激动作用降低的合理性，我们对三种配体与 μ-阿片受体（MOR）结合后的 MOR 进行了长期的分子动力学模拟：吗啡、TRV130 和 PZM21。我们发现，W293（Ballesteros-Weinstein 编号）侧链的延迟运动是决定 PZM21 剂量依赖性激动作用的一个因素。W318、Y326 和 Y336 构象变化的差异解释了这些配体之间观察到的偏向差异。穿过受体通道的水分子运动程度与镇痛效果相关。综上所述，这些数据表明，所研究的 MOR-配体复合物构象变化的差异表明，与其他两种配体相比，PZM21 的效力较低，偏向作用较低，为 G 蛋白偏向激动剂的开发奠定了基础。
