Management of moderate to severe pain relies heavily on opioid analgesics such as morphine, oxycodone, and fentanyl in clinics. However, their prolonged use was associated with undesirable side effects. Many new strategies to reduce side effects have been proposed, but not without disadvantages. Using a hot plate model as a phenotypic screening method, our studies identified (3R,4S)-9d with a new scaffold as a potent analgesic with ED₅₀ values of 0.54 mg/kg and 0.021 mg/kg in hot plate and antiwrithing models, respectively. Mechanistic studies showed that it elicited its analgesic effect via the active metabolite (3R,4S)-10a. The mechanism of (3R,4S)-10a-induced activation of the μ opioid receptor (MOR) was proposed by means of molecular dynamics (MD) simulation.

中文翻译：

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1-((3R,4S)-3-((二甲氨基)甲基)-4-羟基-4-(3-甲氧基苯基)哌啶-1-基)-2-( 2,4,5-trifluorophenyl)ethan-1-one 作为一种新型强效镇痛剂

中度至重度疼痛的管理在很大程度上依赖于阿片类镇痛药，例如临床中的吗啡、羟考酮和芬太尼。然而，它们的长期使用与不良副作用有关。已经提出了许多减少副作用的新策略，但并非没有缺点。使用热板模型作为表型筛选方法，我们的研究确定 (3 R ,4 S )- 9d与新支架一起作为有效的镇痛剂，热板和抗扭体中的ED ₅₀值为 0.54 mg/kg 和 0.021 mg/kg模型，分别。机理研究表明，它通过活性代谢物 (3 R ,4 S )- 10 a引起镇痛作用. 通过分子动力学（MD）模拟提出了（3 R ,4 S）- 10 a诱导μ阿片受体（MOR）活化的机制。