Synthesis and in vitro evaluation of a library of modified endomorphin 1 peptides
Synthesis and in vitro evaluation of a library of modified endomorphin 1 peptides
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DOI：
10.1016/j.bmc.2008.04.020
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发表时间：
2008-06-01
影响因子：
3.5
通讯作者：
Blanchfield, Joanne T.
中科院分区：
文献类型：
--
作者：
Koda, Yasuko;Del Borgo, Mark;Blanchfield, Joanne T.
内吗啡肽1（Endo-1 = Tyr-Pro-Trp-Phe-NH（2））是一种对μ阿片受体具有高亲和力和选择性的内源性阿片类药物，介导啮齿动物的急性和神经性疼痛。为了克服代谢不稳定性和差的膜渗透性，用脂氨基酸（Laa）和/或糖修饰Endo-1的N-和C-末端，并用2 '，6'-二甲基酪氨酸（Dmt）替换Tyr。评估类似物的μ-阿片受体亲和力、cAMP积累抑制、酶稳定性和跨Caco-2细胞单层的渗透性。C-末端阳离子降低了受体亲和力，而N-末端C8-Laa改善了稳定性和渗透性，受体亲和力略有变化。Dmt提供了一种有前景的先导化合物：[C8 Laa-Dmt [1]]-Endo-1的稳定性提高了9倍（t（1/2）= 43.5 min），在Caco-2细胞单层中的渗透性提高了>8倍，并且表现出140倍的μ阿片受体亲和力（K（i mu）= 0.08 nM）。(C)2008爱思唯尔有限公司保留所有权利。
Endomorphin 1 (Endo-1 = Tyr-Pro-Trp-Phe-NH(2)), an endogenous opioid with high affinity and selectivity for mu-opioid receptors, mediates acute and neuropathic pain in rodents. To overcome metabolic instability and poor membrane permeability, the N- and C-termini of Endo-1 were modified by lipoamino acids (Laa) and/or sugars, and 2',6'-dimethyltyrosine (Dmt) replacement of Tyr. Analogues were assessed for mu-opioid receptor affinity, inhibition of cAMP accumulation, enzymatic stability, and permeability across Caco-2 cell monolayers. C-Terminus modi. cation decreased receptor affinity, while N-terminus C8-Laa improved stability and permeability with slight change in receptor affinity. Dmt provided a promising lead compound: [C8Laa-Dmt[1]]-Endo-1 is nine times more stable (t(1/2) = 43.5 min), >8- fold more permeable in Caco-2 cell monolayers, and exhibits 140-fold greater mu-opioid receptor affinity (K(i mu) = 0.08 nM). (C) 2008 Elsevier Ltd. All rights reserved.