STRUCTURE/ACTIVITY STUDIES OF NEUROSTEROID ANALOGS

麻醉剂类固醇已被证明在GABAA起作用 受体/氯通道复合体促进心肌细胞超极化 GABA能神经元。目前认为，这种相互作用是 麻醉剂类固醇作用的分子机制。可调的 麻醉剂和其他神经活性类固醇在附加离子时的作用 渠道也是已知的。在多大程度上， 这些额外离子通道上的麻醉性类固醇有助于 类固醇诱导的麻醉尚不清楚。这样做的具体目的是 提案的重点是获得关于分子的新知识 这些类固醇与GABAA受体相互作用的细节 复合离子通道和其他离子通道。合成化学将成为 用于制备新的类固醇类似物和对映体 神经活性类固醇。GABAA的构效关系 将使用计算方法来分析受体的调制 构象分子场分析。类固醇对映体 将用于区分受体介导的效应和 膜扰动效应。这些化合物将被评估 使用电生理、结合和行为分析。神经活性 已知增加GABA介导的氯电流的类固醇 有麻醉剂、抗惊厥药、抗焦虑药和镇静催眠药 效果。其他离子通道上的作用和/或 这些化合物对膜的扰动作用是什么 神经活性类固醇的药理作用还不确定。这个 这个项目的长期目标是使用医学的方法 化学将获得新的药理工具来研究其影响 GABAA受体和其他类型离子的神经活性类固醇 频道。最终，这些信息可能会导致发现 新型麻醉剂、抗惊厥药、抗焦虑药和镇静催眠药。

Anesthetic steroids have been shown to act at the GABAa receptor/chloride channel complex to facilitate hyperpolarization of GABAergic neurons. It is currently thought that this interaction is the molecular mechanism of action of anesthetic steroids. Modulatory effects of anesthetic and other neuroactive steroids at additional ion channels are also known. The extent to which the actions of anesthetic steroids at these additional ion channels contributes to steroid-induced anesthesia is not yet clear. The specific aims of this proposal are focused on gaining new knowledge of the molecular details of the interactions of these steroids with the GABAA receptor complex and other ion channels. Synthetic chemistry will be performed to prepare novel steroid analogues and enantiomers of neuroactive steroids. Structure-activity relationships for GABAA receptor modulation will be analyzed using the computational method of Conformational Molecular Field Analysis. The steroid enantiomers will be used to distinguish between receptor-mediated effects and membrane perturbation effects. These compounds will be evaluated using electrophysiological, binding, and behavioral assays. Neuroactive steroids that increase GABA-mediated chloride current are known to have anesthetic, anticonvulsant, anxiolytic, and sedative hypnotic effects. The extent to which actions at other ion channels and/or to which membrane perturbing effects by these compounds contributes to the pharmacologic profile of neuroactive steroids is uncertain. The long term goals of this project are to use the methods of medicinal chemistry to obtain new pharmacological tools to investigate the effects of neuroactive steroids at GABAA receptors and other types of ion channels. Ultimately, this information could lead to the discovery of new anesthetic, anticonvulsant, anxiolytic, and sedative hypnotic drugs.