Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Department of Pharmacology, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University , Lanzhou 730000, P. R. China.
ACS Chem Neurosci. 2017 Oct 18;8(10):2180-2193. doi: 10.1021/acschemneuro.7b00097. Epub 2017 Aug 10.
Opioid peptides are neuromodulators that bind to opioid receptors and reduce pain sensitivity. Endomorphins are among the most active endogenous opioid peptides, and they have good affinity and selectivity toward the μ opioid receptor. However, their clinical usage is hindered by their inability to cross the blood-brain barrier and their poor in vivo activity after peripheral injection. In order to overcome these defects, we have designed and synthesized a series of novel endomorphin analogs with multiple site modifications. Radioligand binding, cAMP accumulation, and β-arrestin-2 recruitment assays were employed to determine the activity of synthesized endomorphin analogs toward opioid receptors. The blood-brain barrier permeability and antinociceptive effect of these analogs were determined in several rodent models of acute and persistent pain. In addition, the side effects of the analogs were examined. The radioligand binding assay and functional activity examination indicated that the MEL-N16 series of compounds were more active agonists against μ opioid receptor than were the parent peptides. Notably, the analogs displayed biased downstream signaling toward G-protein pathways over β-arrestin-2 recruitment. The analogs showed highly potent antinociceptive effects in the tested nociceptive models. In comparison with endomorphins, the synthesized analogs were better able to penetrate the blood-brain barrier and exerted their pain regulatory activity in the central nervous system after peripheral injection. These analogs also have lower tendency to cause side effects than morphine does at similar or equal antinociceptive doses. The MEL-N16 compounds have highly potent and efficacious analgesic effects in various pain models with a favorable side effect profile.
阿片肽是与阿片受体结合并降低痛觉敏感性的神经调节剂。内吗啡肽是最活跃的内源性阿片肽之一，它们对 μ 阿片受体具有良好的亲和力和选择性。然而，由于它们不能穿过血脑屏障，并且在外周注射后体内活性较差，因此它们的临床应用受到限制。为了克服这些缺陷，我们设计并合成了一系列具有多个位点修饰的新型内吗啡肽类似物。放射性配体结合、cAMP 积累和β-arrestin-2 募集测定用于测定合成的内吗啡肽类似物对阿片受体的活性。在几种急性和持续性疼痛的啮齿动物模型中，测定了这些类似物的血脑屏障通透性和抗伤害作用。此外，还检查了类似物的副作用。放射性配体结合测定和功能活性检测表明，MEL-N16 系列化合物作为 μ 阿片受体的激动剂比母体肽更具活性。值得注意的是，与β-arrestin-2 募集相比，这些类似物表现出对 G 蛋白途径的偏向下游信号传导。类似物在测试的伤害感受模型中显示出高度有效的抗伤害作用。与内吗啡肽相比，合成的类似物能够更好地穿透血脑屏障，并在外周注射后在中枢神经系统中发挥其疼痛调节活性。与吗啡在类似或相等的镇痛剂量下相比，这些类似物引起副作用的倾向也较低。MEL-N16 化合物在各种疼痛模型中具有高效、有效的镇痛作用，副作用谱良好。
