前药
体内
硫胺素
化学
AMPA受体
药理学
体外
分布(数学)
血脑屏障
谷氨酸受体
生物化学
受体
医学
生物
内科学
中枢神经系统
数学分析
生物技术
数学
作者
Dian Xiao,Fanhua Meng,Wei Dai,Yongchang Zheng,Jinqiu Liu,Xinbo Zhou,Song Li
出处
期刊:Molecules
[MDPI AG]
日期:2016-04-14
卷期号:21 (4): 488-488
被引量:8
标识
DOI:10.3390/molecules21040488
摘要
Ampakine compounds have been shown to reverse opiate-induced respiratory depression by activation of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors. However, their pharmacological exploitations are hindered by low blood-brain barrier (BBB) permeability and limited brain distribution. Here, we explored whether thiamine disulfide prodrugs with the ability of “lock-in” can be used to solve these problems. A series of thiamine disulfide prodrugs 7a–7f of ampakine compound LCX001 was synthesized and evaluated. The trials in vitro showed that prodrugs 7e, 7d, 7f possessed a certain stability in plasma and quickly decomposed in brain homogenate by the disulfide reductase. In vivo, prodrug 7e decreased the peripheral distribution of LCX001 and significantly increased brain distribution of LCX001 after i.v. administration. This compound showed 2.23- and 3.29-fold greater increases in the AUC0-t and MRT0-t of LCX001 in brain, respectively, than did LCX001 itself. A preliminary pharmacodynamic study indicated that the required molar dose of prodrug 7e was only one eighth that of LCX001 required to achieve the same effect in mice. These findings provide an important reference to evaluate the clinical outlook of ampakine compounds.
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