阿片类药物芬太尼及其衍生物是临床上最常使用的一类麻醉剂，但其呼吸抑制、胃肠功能紊乱、耐受等副作用限制了该类药物的使用，其中呼吸抑制是芬太尼类药物致死的主要原因。近年研究指出，吗啡作用于μ阿片受体所产生的呼吸抑制等副反应主要通过β-arrestin通路介导，而镇痛作用则由G蛋白通路介导，且在此理论基础上，成功发现了副作用减轻的新型阿片类镇痛药。据此假设，芬太尼类药物的镇静麻醉作用与呼吸抑制等副作用也分别由μ阿片受体下游的不同信号通路介导，且μ阿片受体中的某些氨基酸位点可能会影响信号通路的偏倚。由此，我们拟从受体结构和受体后信号通路两个层面研究芬太尼类与μ阿片受体相互作用产生不同药理效应的机制，阐明芬太尼类化合物与μ阿片受体相互作用的关键性氨基酸位点以及位点与信号通路之间的关系，为阿片类药物的作用机制补充思路，为设计新型副作用更小的阿片类麻醉药提供线索。

Opioids Fentanyl and its derivatives are among the most used clinical anesthetics, but various side effects—which include respiratory suppression, gastrointestinal dysfunction and tolerance—set a limit to medication. It is reported that side effects of morphine are mediated through β-arrestin pathway while G-protein signaling is thought to confer analgesia. Based on the theory, a novel analgesic with reduced side effects—PZM21 was successfully synthesized. Similarly, the sedation and respiratory depression of fentanyl derivatives may be mediated through different signal pathways, and some amino acid sites of μ-opioid receptor may influence signaling bias. Accordingly, in this project, we intend to unravel the critical amino acid sites of μ-opioid receptor interacting with fentanyl derivatives and illustrate the molecular mechanisms governing the nature of ligand-receptor binding and signaling bias. If we clarify the relationship between amino acid sites and signaling, the detailed mechanisms of opioids can be further elucidated, which contribute to the design and synthesis of novel opioid anesthetics with reduced side effects.