MOLECULAR & BEHAVIORAL NEUROPHARMACOLOGY OF BUTYROLACTONES & RELATED COMPOUNDS

分子

• 批准号: 6112107
• 负责人: JAMES A FERRENDELLI
• 金额: --
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6112107
• 关键词: GABA receptor; anticonvulsants; brain electrical activity; butyrolactone; chemical binding; chloride channels; convulsants; drug receptors; laboratory mouse; laboratory rat; neuropharmacology; neurotoxins; picrotoxin; psychopharmacology; receptor binding; receptor sensitivity

several important, widely used neurotropic drugs including benzodiazepines, barbiturates, neurosteroids and others produce their effects by acting at the GABA-A receptor-chloride ionophore. Recently we discovered a new class of neuroactive chemicals, alkyl-substituted butyrolactones, which can also modulate GABA mediated chloride conductances. These compounds appear to have a mechanism and site of action at the GABA-A receptor- chloride ionophore which is clearly different from the other compounds noted above. The major goals of this proposed project are to characterize mechanisms and sites of action and behavioral effects of neuroactive butyrolactones and related compounds. This project tests the hypothesis that butyrolactones have specific actions and effects on neuronal activity in brain, which are different from other substances known to regulate CNS neuronal activity. The specific aims of this project are: 1. To define and characterize the neurologic and behavioral effects of neuroactive butyrolactones and related compounds. Individual compounds will be studied extensively to characterize their anticonvulsant, anxiolytic, sedative/hypnotic and other neurologic and behavioral effects as well as their acute and chronic effects in an attempt to identify agents with high therapeutic potential. All studies will be performed on rats and mice. 2. To identify the sites and mechanisms of action of neuroactive butyrolactones and structurally related compounds. The binding characteristics of several selected butyrolactones will be studied in detail and we will attempt to determine whether or not the butyrolactone and picrotoxin effector sites are identical. We will attempt to define where butyrolactones act. We hope to employ newly developed butyrolactone radioligands. All these experiments will utilize tissues from rats or mice. We will also attempt to identify where butyrolactones act on the GABA-A receptor-chloride ionophore using molecular biology techniques and methods and receptor binding experiments. In addition, we will attempt to determine whether butyrolactones have an effector site on other ligand gated channels. The study of butyrolactones and related compounds can improve understanding of the GABA-A receptor-chloride ionophore, help explain normal and abnormal CNS function and help identify new neurotropic drugs useful for the treatment of several neurologic and psychiatric diseases and disorders.

几种重要的、广泛使用的亲神经性药物， 苯二氮卓类、巴比妥类、神经甾体类和其他药物产生它们的 作用于GABA-A受体-氯离子载体。 最近我们 发现了一类新的神经活性化学物质，烷基取代的 丁内酯，也可以调节GABA介导的氯化物 电导率这些化合物似乎有一个机制和网站， 作用于GABA-A受体-氯离子载体， 与上述其他化合物不同。本项目的主要目标是 拟议的项目是确定机制和行动地点的特点， 神经活性丁内酯和相关化合物的行为效应。 该项目测试的假设，丁内酯具有特定的 对大脑神经元活动的作用和影响，这是不同的 与其他已知调节中枢神经系统神经元活动的物质不同。的 该项目的具体目标是： 1.定义和描述的神经和行为的影响， 神经活性丁内酯和相关化合物。单个化合物 将被广泛研究以表征其抗惊厥剂， 抗焦虑、镇静/催眠和其他神经和行为作用 以及它们的急性和慢性影响， 具有高治疗潜力的药物。所有研究将在 大鼠和小鼠。 2.确定神经活性物质的作用部位和机制， 丁内酯和结构上相关的化合物。 的结合 几种选定的丁内酯的特性将在 我们将尝试确定丁内酯是否 和印防己毒素效应位点是相同的。我们将尝试定义 其中丁内酯起作用。我们希望采用新开发的丁内酯 放射性配体。所有这些实验都将利用来自大鼠或 小鼠我们还将尝试确定丁内酯作用于 GABA-A受体-氯离子载体的研究 方法和受体结合实验。此外，我们将努力 确定丁内酯是否在其他配体上具有效应位点 门控通道 对丁内酯及其相关化合物的研究可以提高 了解GABA-A受体-氯离子载体，有助于解释 正常和异常的中枢神经系统功能，并帮助确定新的亲神经药物 用于治疗几种神经和精神疾病 和失调