MOLECULAR & BEHAVIORAL NEUROPHARMACOLOGY OF BUTYROLACTONES & RELATED COMPOUNDS

几种重要的、广泛使用的神经趋化药物包括 苯二氮卓类药物、巴比妥类药物、神经类固醇类药物和其他药物 作用于GABA-A受体-氯离子载体的效应。最近我们 发现了一类新的神经活性化学物质，烷基取代 丁内酯，也可调节GABA介导的氯离子 导电性。这些化合物似乎有一个机制和位置 作用于GABA-A受体-氯离子载体 与上述其他化合物不同。这次会议的主要目标是 拟议的项目是描述行动的机制和地点，并 神经活性丁内酯及其相关化合物的行为效应。 这个项目测试了丁内酯具有特异性的假设。 对大脑中神经元活动的作用和影响是不同的 从其他已知的调节中枢神经系统神经活动的物质中分离出来。这个 该项目的具体目标是： 1.定义和描述神经和行为的影响 神经活性丁内酯及其相关化合物。个别化合物 将被广泛研究以确定其抗惊厥的特性， 抗焦虑、镇静/催眠及其他神经和行为影响 以及它们的急性和慢性影响，试图确定 具有很高治疗潜力的药物。所有研究都将在 老鼠和老鼠。 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。装订 几种选定的丁内酯的特性将在#年进行研究 我们将尝试确定丁内酯是否 和印防己毒素的效应点是一样的。我们将尝试定义 丁内酯起作用的地方。我们希望使用新开发的丁内酯 放射性配基。所有这些实验都将利用大鼠或 老鼠。我们还将尝试确定丁内酯在哪里作用于 用分子生物学技术研究GABA-A受体-氯离子载体 方法和受体结合实验。此外，我们还将尝试 确定丁内酯是否在其他配体上有效应部位 门控频道。 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 中枢神经系统功能正常和异常，有助于发现新的神经递质药物 用于治疗几种神经和精神疾病 和精神障碍。

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.