STRUCTURE/ACTIVITY STUDIES OF NEUROSTEROID ANALOGS

麻醉类固醇已被证明对GABA a起作用 受体/氯离子通道复合物，以促进 GABA能神经元。 目前认为这种相互作用是 麻醉类固醇作用的分子机制。 调节 麻醉剂和其他神经活性类固醇对额外离子的影响 信道也是已知的。 在多大程度上， 这些额外离子通道的麻醉类固醇有助于 类固醇引起的麻醉还不清楚。 具体目标是 建议的重点是获得新的知识的分子 这些类固醇与GABAA受体相互作用的详细信息 复合物和其他离子通道。 合成化学将是 进行，以制备新的类固醇类似物和对映异构体 神经活性类固醇 GABAA的构效关系 受体调制将使用计算方法进行分析 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， 膜扰动效应 将对这些化合物进行评价 使用电生理学、结合和行为分析。 神经活性 已知增加GABA介导的氯离子电流的类固醇 有麻醉剂、抗惊厥药、抗焦虑药和镇静催眠药 方面的影响. 对其他离子通道和/或对 这些化合物的膜扰动效应有助于 神经活性类固醇的药理学特征是不确定的。 的 该项目的长期目标是使用药物的方法， 化学，以获得新的药理学工具，以研究影响 神经活性类固醇在GABAA受体和其他类型的离子 渠道 最终，这些信息可能会导致发现 新的麻醉药、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.