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:
  • 金额:
    $ 4.67万
  • 依托单位:
  • 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
动物大脑中的3α-羟基类固醇脱氢酶(HSD)和20α-HSD已被证明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症、经期癫痫和抑郁症等疾病的证据。本研究重点关注以下六点,以两种人类酶为目标,开发治疗此类疾病的新药。1.人类酶在神经类固醇代谢中的作用。酶的组织分布和对神经类固醇的底物特异性表明,在大脑中20α-HSD使神经活性类固醇及其前体黄体酮失活,并且3α-HSD 3型参与神经活性类固醇的合成。2.寻找激活剂和抑制剂。只有 3α-HSD 1 型被几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特异性强地抑制20α-HSD,这表明它们是开发该药物的先导化合物。3.酶的结构-功能关系。 20α-HSD 和 3α-HSD 1 型的定点诱变研究鉴定或提出了其活性中心的几个氨基酸以及激活剂和抑制剂的结合位点。 20α-HSD的晶体学研究正在进行中。 4.基因表达的调节。在几种培养的人类细胞中,依他尼酸增强了除 1 型 3α-HSD 之外的酶的表达。肝脏特异性3α-HSD 1型表达的研究表明,3种肝细胞核因子调控该酶基因的转录。5.遗传多态性。对标本中3α-HSD 1型表达的mRNA和基因进行分析,鉴定出编码低催化活性酶的变异基因。6.利用转染酶或其基因的细胞和动物建立药物评价体系利用细胞建立了评价体系,但利用动物模型无法实现,因为酶的表达量太少,无法影响脑功能。后一制度的建立将继续进行。较少的

项目成果

期刊论文数量(40)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
白石弘章: "日本人における3α-ヒドロキシステロイド脱水素酵素の遺伝的多型性"DNA多型. 8. 75-78 (2000)
Hiroaki Shiraishi:“日本 3α-羟基类固醇脱氢酶的基因多态性”DNA 多态性。 8. 75-78 (2000)
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    0
  • 作者:
  • 通讯作者:
T.Kume et al.: "Characterization of a novel variant(S145C/L311V)of 3α-hydroxystaroid/dihydrodiol dehydrogenase in human liver"Pharmacogenetics. 9・. 763-771 (1999)
T. Kume 等人:“人肝脏中 3α-羟基类星形酸/二氢二醇脱氢酶的新型变体(S145C/L311V)的表征”药物遗传学 9·763-771(1999 年)。
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    0
  • 作者:
  • 通讯作者:
T.Ozeki: "Co-operative regulation of the transcription of human dihydrodiol dehydrogenase (DD)/aldo-keto reductase (AKR)1C4 gene by hepatocyte nuclear factor (HNF)-4α/γ and HNF-1α"Biochem.J.. 355. 537-544 (2001)
T.Ozeki:“肝细胞核因子 (HNF)-4α/γ 和 HNF-1α 协同调控人二氢二醇脱氢酶 (DD)/醛酮还原酶 (AKR)1C4 基因的转录”Biochem.J.。 355. 537-544 (2001)
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    0
  • 作者:
  • 通讯作者:
T.Kume: "Characterization of a novel variant (S145C/L311V) of 3α-hydroxysteroid/dihydrodiol dehydrogenase in human liver"Pharmacogenetics. 9. 763-771 (1999)
T.Kume:“人肝脏中 3α-羟基类固醇/二氢二醇脱氢酶的新型变体 (S145C/L311V) 的表征”药物遗传学 9. 763-771 (1999)
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    0
  • 作者:
  • 通讯作者:
N.Usami: "Substrate specificity of human 3(20)α-hydroxysteroid dehydrogenase for neurosteroids and inhibition by benzodiazepines"Biol.Pharm.Bull.. 25(印刷中). (2002)
N.Usami:“人 3(20)α-羟基类固醇脱氢酶对神经类固醇的底物特异性和苯二氮卓类药物的抑制”Biol.Pharm.Bull.. 25(印刷中)。
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  • 影响因子:
    0
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HARA Akira其他文献

HARA Akira的其他文献

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{{ truncateString('HARA Akira', 18)}}的其他基金

Automatic Generation of Graph-structural Programs by Using Swarm Intelligence of Ants
利用蚂蚁群体智能自动生成图结构程序
  • 批准号:
    25730149
  • 财政年份:
    2013
  • 资助金额:
    $ 4.67万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
DEVELOPMENT OF ANTITUMOR DRUGS TARGETING TUMOR MARKERALDO-KETO REDUCTASES
开发针对肿瘤标记酮还原酶的抗肿瘤药物
  • 批准号:
    22590102
  • 财政年份:
    2010
  • 资助金额:
    $ 4.67万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The market economy and the system design of 20th century Japan
市场经济与20世纪日本的制度设计
  • 批准号:
    20243023
  • 财政年份:
    2008
  • 资助金额:
    $ 4.67万
  • 项目类别:
    Grant-in-Aid for Scientific Research (A)
Neuron-Like Differentiation and Selective Ablation of Undifferentiated Embryonic Stem Cells Containing Suicide Gene with Oct-4 Promoter
含有Oct-4启动子自杀基因的未分化胚胎干细胞的神经元样分化和选择性消融
  • 批准号:
    19592012
  • 财政年份:
    2007
  • 资助金额:
    $ 4.67万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Firms and Industrial Association in the Period of the Second World War and the Postwar Economic Recovery
第二次世界大战期间的企业和工业协会以及战后经济复苏
  • 批准号:
    16203025
  • 财政年份:
    2004
  • 资助金额:
    $ 4.67万
  • 项目类别:
    Grant-in-Aid for Scientific Research (A)
Study on the uronate-cycle oxidoreductases that are expressed highly in kidney
肾脏高表达糖醛酸循环氧化还原酶的研究
  • 批准号:
    13672290
  • 财政年份:
    2001
  • 资助金额:
    $ 4.67万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Study of tissue-specific dihydrodiol dehydrogenase
组织特异性二氢二醇脱氢酶的研究
  • 批准号:
    11672175
  • 财政年份:
    1999
  • 资助金额:
    $ 4.67万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Cochlear Dysfunction and Free Radicals : hydroxyl radicals, metallic elements, steroid hormones and SOD
耳蜗功能障碍和自由基:羟基自由基、金属元素、类固醇激素和 SOD
  • 批准号:
    10470351
  • 财政年份:
    1998
  • 资助金额:
    $ 4.67万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Structures and clinical significance of polymorphism of human dihydrodiol dehydrogenase
人二氢二醇脱氢酶多态性的结构及临床意义
  • 批准号:
    09672240
  • 财政年份:
    1997
  • 资助金额:
    $ 4.67万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The decontrol and the restoration to the market economy after The World War II
二战后放松管制和恢复市场经济
  • 批准号:
    09430014
  • 财政年份:
    1997
  • 资助金额:
    $ 4.67万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)

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Hormonal Contraceptives and Adolescent Brain Development
激素避孕药和青少年大脑发育
  • 批准号:
    10668018
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睡眠剥夺引起的信息处理和执行缺陷的机制
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创伤性脑损伤的性别差异:重叠压力和物理效应的神经回路调节因素
  • 批准号:
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Neurosteroid and Cholesterol Binding to Integral Membrane Proteins
神经类固醇和胆固醇与整合膜蛋白的结合
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    10623887
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