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BASIC MECHANISMS OF SEIZURES

癫痫发作的基本机制

基本信息

批准号：
2891571
负责人：
JAMES A FERRENDELLI
金额：
$ 94.94万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
1979
资助国家：
美国
起止时间：
1979-01-01 至 2002-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2891571
关键词：
GABA receptor anticonvulsants brain electrical activity butyrolactone

项目摘要

This is a proposal to continue a very successful and highly productive program project entitled "Basic Mechanisms of Seizures". The overall goal of this program is to characterize structure-activity relationships, mechanisms and sites of action, and neurologic effects of alkyl- substituted butyrolactones and related compounds--a newly discovered class of neuroactive chemicals. Initial studies have demonstrated that these compounds can modulate the action of GABA, the major inhibitory neurotransmitter in mammalian CNS, by affecting its action at the GABA-A receptor-chloride ionophore. Several highly effective and widely used neurotropic drugs, particularly benzodiazepines and barbiturates, also act at the GABA-A receptor. This program tests the hypothesis that alkyl substituted butyrolactones have sites and mechanisms of action different from other compounds acting at the GABAA receptor-chloride ionophore and as a result of these distinct actions, these compounds have considerable potential for development as improved neurotropic therapeutic agents. The present program consists of three integrated component projects, a scientific (molecular biology) core and an administrative core. The major goals of the component projects are: 1 )To identify and synthesize new neuroactive alkyl-substituted butyrolactones and structurally related compounds and characterize their structure-activity relationships 2) To characterize the molecular sites and mechanisms of action and neurologic effects of alkyl-substituted butyrolactones and related compounds; and 3) To characterize the functional sites and mechanisms of action of alkyl- substituted butyrolactones and related compounds. These studies will utilize synthetic organic chemistry, neuropharmacology, electrophysiology, molecular biology and neuroanatomical methods and techniques. Our program brings together a group of experienced, talented and productive medical scientists who have special knowledge and research skills which make them particularly suited to carry out our goals. We have already demonstrated that we can work well together and can direct closely inter-related and complementary research projects. Our research should improve the understanding of the GABA-A receptor- chloride ionophore and other receptors in brain, help explain normal and abnormal GNS function and identify new drugs for the treatment of neurologic and psychiatric disorders including seizures and epilepsy.

这是一项继续非常成功和富有成效的提议题为“癫痫发作的基本机制”的方案项目。总目标这一计划的目的是表征结构-活性关系，烷基化合物的作用机制、作用部位及神经学效应取代丁内酮及其相关化合物--一类新发现的化合物神经活性化学物质。初步研究表明，这些化合物可以调节GABA的作用，GABA是主要的抑制物哺乳动物中枢神经系统中的神经递质通过影响其在GABA-A上的作用受体-氯离子载体。几个高效、应用广泛的嗜神经性药物，特别是苯二氮卓类药物和巴比妥类药物也起作用。在GABA-A受体上。这个程序测试了烷基的假设取代丁内酯具有不同的作用部位和作用机理与作用于GABAA受体的其他化合物-氯离子载体和由于这些不同的作用，这些化合物具有相当大的作为改进的嗜神经治疗药物的开发潜力。本方案包括三个综合组成部分项目，一个科学(分子生物学)核心和行政核心。少校组成项目的目标是：1)确定和综合新的神经活性烷基取代丁内酯及其结构关系化合物并表征其构效关系2)至描述作用和神经学的分子部位和机制烷基取代丁内酯及其相关化合物的作用；为了表征烷基的官能团和作用机理，取代丁内酮及其相关化合物。这些研究将利用合成有机化学，神经药理学，电生理学，分子生物学和神经解剖学的方法和技术。我们的节目汇聚了一群经验丰富、才华横溢、富有成效的医生拥有特殊知识和研究技能的科学家使他们特别适合实现我们的目标。我们已经演示过了我们可以很好地合作，可以指导密切相关的和互补性研究项目。我们的研究应该会提高对GABA-A受体的理解- 大脑中的氯离子载体和其他受体，有助于解释正常和神经节细胞功能异常与寻找治疗糖尿病新药神经和精神障碍，包括癫痫发作和癫痫。

项目成果

期刊论文数量（107）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dual modulation of the gamma-aminobutyric acid type A receptor/ionophore by alkyl-substituted gamma-butyrolactones.

烷基取代的γ-丁内酯对γ-氨基丁酸A型受体/离子载体的双重调节。

DOI：
发表时间：
1995
期刊：
Molecular pharmacology.
影响因子：
0
作者：
Holland,KD;Mathews,GC;Bolos-Sy,AM;Tucker,JB;Reddy,PA;Covey,DF;Ferrendelli,JA;Rothman,SM
通讯作者：
Rothman,SM

Role of the fastigial nucleus in generalized seizures as demonstrated by GABA agonist microinjections.

GABA 激动剂显微注射证明顶核在全身性癫痫发作中的作用。