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Development of drugs targeting neurosteroid-metabolizing enzymes

开发针对神经类固醇代谢酶的药物

基本信息

批准号：
11557195
负责人：
HARA Akira
金额：
$ 4.67万
依托单位：
Gifu Pharmaceutical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

项目摘要

3α-Hydroxysteroid dehydrogenase (HSD) and 20α-HSD in animal brains have been shown to be involved in the synthesis and metabolism of neuroactive steroids. In humans, one 20α-HSD and three 3α-HSDs (type 1 - 3) are present, and the roles of the enzymes in the neurosteroid metabolism are unknown, but clinical investigations provide evidence for an involvement of the neuroactive steroids in conditions such as premenstrual syndrome, catamenial epilepsy and depressive disorders. This study focused the following six points on the two human enzymes as targets for developing new drugs for management of such disorders.1. Roles of the human enzymes in the neurosteroid metabolism. Tissue distribution and substrate specificity for neurosteroids of the enzymes suggest that in the brain 20α-HSD inactivates the neuroactive steroids and their precursor, progesterone, and that 3α-HSD type 3 is involved in the synthesis of the neuroactive steroids.2. Search of activators and inhibitors. Only 3α-HSD type … More 1 was activated by several therapeutic drugs and thyroxine. Of several inhibitors for the enzymes, benzbromarone and its derivatives specifically and strongly inhibited 20α-HSD, which suggests that they are lead compounds to develop the drugs.3. Structure-function relationship of the enzymes. The site-directed mutagenesis study of 20α-HSD and 3α-HSD type 1 identified or suggested several amino acids in their active centers and binding sites for the activators and inhibitors. The crystallographic study of 20α-HSD is now in progress.4. Regulation of gene expression. Ethacrynic acid enhanced the expression of the enzymes, except 3α-HSD type 1 in several cultured human cells. The investigation of expression of liver-specific 3α-HSD type 1 indicated that three hepatocyte nuclear factors regulate the transcription of the enzyme gene.5. Genetic polymorphism. Analyses of expressed mRNA and gene for 3α-HSD type 1 in specimens identified a variant gene which encodes a enzyme with low catalytic activity.6. Establishment of evaluation system for drugs using cells and animals transfected with the enzymes or their genes The system using the cells was established, but that using the animal models could not be achieved, because the expression of the enzyme was too little to affect the brain function. The establishment of the latter system will be continued. Less

动物脑中的3α-羟基类固醇脱氢酶（3α-Hydroxysteroid dehydrogenase，HSD）和20α-HSD参与神经活性类固醇的合成和代谢。在人类中，存在一种20α-HSD和三种3α-HSD（1 - 3型），这些酶在神经类固醇代谢中的作用尚不清楚，但临床研究提供了神经活性类固醇参与经前综合征、月经性癫痫和抑郁症等疾病的证据。这项研究集中在以下六点上的两种人类酶作为开发新的药物来管理这种疾病的目标。人类酶在神经类固醇代谢中的作用。这些酶的组织分布和对神经甾体的底物特异性表明，在脑中20α-HSD使神经活性甾体及其前体孕酮失活，而3α-HSD 3型参与神经活性甾体的合成.搜索激活剂和抑制剂。仅3α-HSD型 ...更多信息 1被多种治疗药物和甲状腺素激活。在几种酶抑制剂中，苯溴马隆及其衍生物对20α-HSD有较强的特异性抑制作用，有望成为开发该类药物的先导化合物.酶的结构-功能关系。20个α-HSD和3个α-HSD 1型的定点突变研究确定或提示了它们的活性中心和激活剂和抑制剂的结合位点中的几个氨基酸。20α-HSD的晶体学研究正在进行中.基因表达调控。在几种培养的人细胞中，除3α-HSD 1型外，依他尼酸增强了酶的表达。对肝特异性3α-HSD 1型表达的研究表明，三种肝细胞核因子调控该酶基因的转录.遗传多态性。对标本中表达的3α-HSD 1型mRNA和基因进行分析，鉴定出一个编码低催化活性酶的变异基因.使用转染了酶或其基因的细胞和动物的药物评价系统的建立使用细胞的系统已经建立，但是使用动物模型的系统无法实现，因为酶的表达太少而不会影响脑功能。将继续建立后一系统。少