Zadina James E, Szabo Lajos Z, Al-Obeidi Fahad, Zhang Xing, Ferreira Nakatani Leticia, Ogbu Chidiebere, Heien M Leandro, Falk Torsten, Bartlett Mitchell J, Polt Robin
Department of Medicine and Pharmacology and Brain Institute, Tulane University School of Medicine, New Orleans, Louisiana 70112, United States.
SE Louisiana Veterans Health Care System, New Orleans, Louisiana 70119, United States.
ACS Med Chem Lett. 2024 Sep 17;15(10):1731-1740. doi: 10.1021/acsmedchemlett.4c00315. eCollection 2024 Oct 10.
Opioids acting at the mu opioid receptor (MOR) remain the most effective treatment for moderate to severe pain, but their use is limited by serious side effects. We have shown that a cyclized analog of endomorphin-1 provided pain relief comparable to that of morphine with reduction or absence of several side effects, including abuse liability. Glycosylation can promote penetration of cellular barriers. Here we developed cyclic glycopeptide endomorphin (glycoEM) analogs as drug candidates for potent and long-lasting analgesia. The analogs were assessed in receptor binding and functional assays and for blood-brain barrier penetration by microdialysis and MS. Two of the analogs showed MOR selectivity and more potent and longer lasting antinociception than morphine in male and female mice. Comparable antinociception occurred at A2 doses 5-fold lower (20-fold on a molar basis) than morphine doses. The results support further study of the glycoEMs for clinical application.
作用于μ阿片受体（MOR）的阿片类药物仍然是治疗中度至重度疼痛最有效的方法，但其使用受到严重副作用的限制。我们已经表明，内吗啡肽-1的环化类似物提供的疼痛缓解效果与吗啡相当，同时减少或消除了包括滥用倾向在内的几种副作用。糖基化可以促进细胞屏障的穿透。在这里，我们开发了环化糖肽内吗啡肽（glycoEM）类似物作为强效和长效镇痛的候选药物。通过微透析和质谱对这些类似物进行受体结合和功能测定以及血脑屏障穿透评估。其中两种类似物在雄性和雌性小鼠中表现出MOR选择性，并且比吗啡具有更强效和更持久的镇痛作用。产生可比镇痛作用的A2剂量比吗啡剂量低5倍（以摩尔计低20倍）。这些结果支持对glycoEMs进行进一步的临床应用研究。
