The effect of halogenation on blood-brain barrier permeability of a novel peptide drug
The effect of halogenation on blood-brain barrier permeability of a novel peptide drug
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DOI：
10.1016/s0196-9781(99)00127-8
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发表时间：
1999-10-01
期刊：
影响因子：
3
通讯作者：
Davis, TP
中科院分区：
文献类型：
--
作者：
Gentry, CL;Egleton, RD;Davis, TP
药物的效用取决于其在靶组织中到达适当受体并保持代谢稳定以产生预期效果的能力。为了改善阿片类镇痛药[o-Pen(2), r-Pen(5), Phe(6)]脑啡肽（DPLPE-Phe）的中枢神经系统进入，本课题组在苯丙氨酸-4残基的对位上合成了含有氯、溴、氟和碘卤素的类似物。本研究报道了卤化对新型脑啡肽类似物DPLPE-Phe的稳定性、亲脂性和体外血脑屏障通透性的影响。在血浆和脑中测试了每种卤化DPLPE-Phe类似物以及经修饰和未修饰的亲本肽的稳定性。除DPLPE-Phe-NH2在血浆中的半衰期为30分钟外，所有测试肽的半衰期均为50 - 300分钟。辛醇/生理盐水分布研究表明，除p-[F-Phe(4)]DPLPE-Phe-OH外，在DPLPE-Phe-OH中添加卤素可显著提高其亲脂性。p-[Cl-Phe(4)]DPLPE-Phe-OH表现出最明显的亲脂性增加。对溴和对氯卤素的添加显著提高了体外血脑屏障的通透性，为改善中枢神经系统的输送提供了证据。(C) 1999 Elsevier Science Inc.；版权所有。
The utility of a drug depends on its ability to reach appropriate receptors at the target tissue and remain metabolically stable to produce the desired effect. To improve central nervous system entry of the opioid analgesic [o-Pen(2), r-Pen(5), Phe(6)] Enkephalin (DPLPE-Phe), our research group synthesized analogs that had chloro, bromo, fluoro, and iodo halogens on the para positions of the phenylalanine-4 residue. This study reports on investigation of the effect of halogenation on stability, lipophilicity, and in vitro blood-brain barrier permeability of a novel enkephalin analog DPLPE-Phe. The stability of each halogenated DPLPE-Phe analog as well as the amidated and nonamidated parent peptide was tested in plasma and brain. All peptides tested had a half-time disappearance >300 min except for DPLPE-Phe-NH2, which was found to have a half-life of 30 min in plasma. Octanol/saline distribution studies indicated addition of halogens to DPLPE-Phe-OH significantly increased lipophilicity except for p-[F-Phe(4)]DPLPE-Phe-OH. p-[Cl-Phe(4)]DPLPE-Phe-OH exhibited the most pronounced increase in lipophilicity. Para-bromo and para-chloro halogen additions significantly enhanced in vitro blood-brain barrier permeability, providing evidence for improved delivery to the central nervous system. (C) 1999 Elsevier Science Inc. All rights reserved.