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Design of Anti-ischemic drug based on their effects in liver mitochondria of the turtle as an anaerobiosis model.

基于对厌氧模型龟肝线粒体的影响设计抗缺血药物。

基本信息

批准号：
02671001
负责人：
HORI Hitoshi
金额：
$ 1.34万
依托单位：
The university of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1990
资助国家：
日本
起止时间：
1990 至 1991
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-02671001/
关键词：
Turtle Anti-ischemic drug Mitochondria Thiodiazole Hypoxia Liver Rat

项目摘要

We designed the following compounds : 1)salicylanilides, 2)thiodiazoles, 3)vitarmin K_1 epoxides, 4)disacchatide sulfates of steroids and triterpenoids(eg. glycyrrhizinic acid), 5)disaccharide(maltose and isomaltose)sulfates, 6)cyclodextrin-steroid complex as candidates of anti-ischemic drugs. Especially we studied the syntheses of new thiadiazole compounds such as TX-101-TX-109, their efftects against the respiratory activity in liver mitochondm in turtle as well as rat, and their in vivo anti-ischemic activity in mouse. We often used the UV detector for HPLC purchased by this grant detect our developed synthetic compounds for their isolation, analysis, and purification. As bioassay, we developed the aninmal model of anti-ischemic drug research using freshwater turtles(Mauremys japonica and Chineinys reevesii)as an animal anaerobe. The liver mitochondria were isolated from liver in turtle which was under hibernation, the RCI(Respiratory Control Index)of which was ca. 3. The mitochondrial function(oxygen consumption and ATP synthesis)was measured in our newly developed cell connected with high-sensitive sensors such as oxygen, pH, and membrane potential. TX-109 uncoupled the mitochondrial oxidative phosphorylation strongly[25nM(Vox max : 14natoms O/min/mg protein)]. This concentration of uncoupling activity in turtle liver mitochondria was similar, but its rate of oxygen consumption at this state was slower, in comparison with those in rat[TX-109 : 45nM(Vox max : 340natoms O/min/mg protein)]. These thiodiazole derivatives TX-101-109 showed weak anti-ischemic activities in vivo at the concentration of l00mg/kg i. p. We approached to develop the animal model using turtle live mitochondria and apply to the development of antiischemic drugs.

我们设计了以下化合物：1）水杨酰苯胺，2）硫代二唑，3）维生素K_1环氧化物，4）类固醇和三萜类化合物（例如甘草酸）的二糖苷硫酸盐，5）二糖（麦芽糖和异麦芽糖）硫酸盐，6）环糊精-类固醇复合物作为抗缺血的候选化合物药物。特别是研究了TX-101-TX-109等新型噻二唑化合物的合成、它们对乌龟和大鼠肝线粒体呼吸活性的影响以及它们在小鼠体内的抗缺血活性。我们经常使用本次资助购买的 HPLC 紫外检测器来检测我们开发的合成化合物，以进行分离、分析和纯化。作为生物测定，我们以淡水龟（日本毛龟和中国龟）作为厌氧动物，建立了抗缺血药物研究的动物模型。从冬眠龟的肝脏中分离出肝线粒体，其RCI（呼吸控制指数）约为。 3. 在我们新开发的细胞中测量线粒体功能（耗氧量和 ATP 合成），并连接氧气、pH 和膜电位等高灵敏度传感器。 TX-109 强烈解偶联线粒体氧化磷酸化[25nM（Vox max：14natoms O/min/mg 蛋白质）]。龟肝线粒体中的解偶联活性浓度相似，但与大鼠相比，该状态下的耗氧速率较慢[TX-109：45nM(Vox max：340natoms O/min/mg Protein)]。这些硫代二唑衍生物TX-101-109在l00mg/kg i浓度下在体内表现出弱的抗缺血活性。 p。我们尝试利用海龟活线粒体开发动物模型，并将其应用于抗缺血药物的开发。