BASIC MECHANISMS OF SEIZURES

这是一项继续进行一项非常成功和富有成效的 题为“癫痫的基本机制”的方案项目。总目标 是表征结构-活性关系， 机制和作用部位，以及烷基- 新发现的一类取代丁内酯及其相关化合物 神经活性化学物质。初步研究表明， 化合物可以调节GABA的作用， 哺乳动物中枢神经系统中的神经递质，通过影响其在GABA-A 受体-氯离子载体。 几种高效且广泛使用的 亲神经药物，特别是苯二氮卓类和巴比妥类药物， GABA-A受体。这个程序测试的假设，烷基 取代的丁内酯具有不同的作用位点和作用机制 来自作用于GABAA受体-氯离子载体的其他化合物， 由于这些不同的作用，这些化合物具有相当大的 作为改进的亲神经性治疗剂的发展潜力。 本方案由三个综合组成项目组成， 科学（分子生物学）核心和行政核心。主要 各组成项目的目标是：1）确定和综合新的 神经活性烷基取代的丁内酯和结构相关的 化合物，并表征其构效关系2） 表征分子位点和作用机制， 烷基取代的丁内酯和相关化合物的影响;以及3） 为了表征烷基化的功能位点和作用机制， 取代的丁内酯和相关化合物。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方法和技术。我们的节目 汇集了一批经验丰富，才华横溢，富有成效的医疗 拥有特殊知识和研究技能的科学家， 特别适合实现我们的目标。我们已经证明了 我们可以很好地合作，可以指导密切相关的， 补充研究项目。 我们的研究应该会提高对GABA-A受体的理解， 氯离子载体和大脑中的其他受体，有助于解释正常的， 异常GNS功能，并确定新的药物用于治疗 神经和精神疾病，包括癫痫发作和癫痫。

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.