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
- 来源:
- 关键词:
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。4.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
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)。
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
HARA Akira其他文献
HARA Akira的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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)
相似海外基金
Hormonal Contraceptives and Adolescent Brain Development
激素避孕药和青少年大脑发育
- 批准号:
10668018 - 财政年份:2023
- 资助金额:
$ 4.67万 - 项目类别:
Unraveling how Lipophilic Modulators Alter pLGIC Function via Interactions with the M4 Transmembrane Helix
揭示亲脂性调节剂如何通过与 M4 跨膜螺旋相互作用改变 pLGIC 功能
- 批准号:
10785755 - 财政年份:2023
- 资助金额:
$ 4.67万 - 项目类别:
Alcohol-induced epigenetic reprogramming of PPAR-α affects allopregnanolone biosynthesis
酒精诱导的 PPAR-α 表观遗传重编程影响异孕酮生物合成
- 批准号:
10658534 - 财政年份:2023
- 资助金额:
$ 4.67万 - 项目类别:
Perinatal Affective Symptoms, Neuroactive Steroids, and GABA Receptor Plasticity in Women of Color
有色人种女性的围产期情感症状、神经活性类固醇和 GABA 受体可塑性
- 批准号:
10572847 - 财政年份:2023
- 资助金额:
$ 4.67万 - 项目类别:
Mechanisms of information-processing and executive deficits caused by sleep deprivation
睡眠剥夺引起的信息处理和执行缺陷的机制
- 批准号:
10886925 - 财政年份:2023
- 资助金额:
$ 4.67万 - 项目类别:
O-GlcNac Modulation of GABAergic Transmission
O-GlcNac 对 GABA 能传输的调节
- 批准号:
10754746 - 财政年份:2023
- 资助金额:
$ 4.67万 - 项目类别:
Structural Basis of Nociceptor Channel TRPM3 gating and pharmacology
伤害感受器通道 TRPM3 门控和药理学的结构基础
- 批准号:
10735377 - 财政年份:2023
- 资助金额:
$ 4.67万 - 项目类别:
Sex differences in traumatic brain injury: Neural circuit mediators of overlapping stress and physical effects
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:
10751089 - 财政年份:2023
- 资助金额:
$ 4.67万 - 项目类别:
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
- 批准号:
10623887 - 财政年份:2023
- 资助金额:
$ 4.67万 - 项目类别:
Adolescent alcohol exposure: impact on neuronal activation, steroids, and metabolomic profiles
青少年酒精暴露:对神经元激活、类固醇和代谢组学特征的影响
- 批准号:
10629731 - 财政年份:2023
- 资助金额:
$ 4.67万 - 项目类别: