Wu Yanjing, Zhao Xinyi, Gan Yongan, Zhang Xuehong, Wei Hongbin, Wang Lewei, Liang Xiaolei, Gao Xuelin, Liu Ying, Hu Junping, Wang Yiqing
The First Hospital of Lanzhou University, Lanzhou 730000, China.
The First Hospital of Lanzhou University, Lanzhou 730000, China; Key Laboratory for Reproductive Medicine and Embryo, Gansu Province, Lanzhou 730000, China.
Bioorg Med Chem Lett. 2017 Apr 1;27(7):1557-1560. doi: 10.1016/j.bmcl.2017.02.034. Epub 2017 Feb 20.
A new class of endomorphin-1 analogues was synthesized by combining successful chemical modifications including N-terminal guanidino modification, Phe was chlorinated, D-Ala-Gly Substituted L-Pro. Their bioactivities were measured by radioligand binding assay, metabolic stability and the tail-flick test. In radioligand binding assays, analogue GAGPC (N-Amidino-Tyr-D-Ala-Gly-Trp-p-Cl-Phe-NH), shown a μ-opioid receptor affinity about 1.42-fold higher and a 2.51-fold higher δ-opioid receptor affinity than EM-1. In the metabolic stability assays, GAGPC had the longest half-lives which was 284min and 53-fold higher than that of EM-1. In the tail-flick test in mice, GAGPC chloride modification increases the lipid content of the drug, thus increases the permeability of the blood brain barrier, and has a higher analgesic activity. It might be of importance in potential application as drug candidates as analgesic.
通过结合成功的化学修饰合成了一类新的内吗啡肽-1类似物，包括N端胍基修饰、苯丙氨酸氯化、用D-丙氨酸-甘氨酸取代L-脯氨酸。通过放射性配体结合试验、代谢稳定性和甩尾试验测定它们的生物活性。在放射性配体结合试验中，类似物GAGPC（N-脒基-酪氨酸-D-丙氨酸-甘氨酸-色氨酸-对氯苯丙氨酸-酰胺）显示出对μ-阿片受体的亲和力比EM-1高约1.42倍，对δ-阿片受体的亲和力高2.51倍。在代谢稳定性试验中，GAGPC的半衰期最长，为284分钟，比EM-1高53倍。在小鼠甩尾试验中，GAGPC的氯化修饰增加了药物的脂溶性，从而增加了血脑屏障的通透性，具有更高的镇痛活性。作为潜在的镇痛候选药物，它可能具有重要的应用价值。
