STRUCTURE/ACTIVITY STUDIES OF NEUROSTEROID ANALOGUES

项目1 GABA-A或NMDA受体的调节是大多数临床使用的麻醉剂的麻醉作用的基础。 全身麻醉药在中枢神经系统中，GABA-A受体功能的增强增加 抑制神经传递和抑制NMDA受体功能降低兴奋性 神经传递麻醉类固醇增强GABA对GABA-A受体的作用。类固醇 含有带负电荷的基团抑制GABA能神经传递。NMDA受体是 通过含有带负电荷的基团的类固醇正或负调节。因此，在本发明中， 了解类固醇在这些受体上的作用对于了解 类固醇类麻醉剂 该项目的三个具体目标是集中在获得分子细节的新知识， 类固醇与GABA-A和NMDA受体的相互作用。将进行合成化学， 制备用于结构-活性关系（SAR）研究的麻醉类固醇的新型类似物。 电生理学、结合和行为分析将用于评价化合物。 具体目标1阐述了类固醇环系统对麻醉类固醇作用的重要性， GABA-A和NMDA受体在具体目标2中，含有荧光基团的麻醉类固醇类似物 将准备：1）研究类固醇如何进入其在跨膜结构域的结合位点， GABA-A受体; 2）研究麻醉类固醇在脑细胞中的进入和分布。具体 目的3将研究麻醉类固醇对GABA-A作用的对映选择性的分子基础 受体。 该项目的长期目标是利用药物化学的方法获得新的 研究类固醇对GABA-A和NMDA受体作用的药理学工具。最后， 这一信息可能导致新的麻醉剂、抗惊厥剂、抗焦虑剂和镇静剂的发现。 催眠药

PROJECT 1 Modulation of GABA-A or NMDA receptors underlies the anesthetic actions of most clinically used general anesthetics. In the central nervous system, enhancement of GABA-A receptor function increases inhibitory neurotransmission and inhibition of NMDA receptor function decreases excitatory neurotransmission. Anesthetic steroids enhance the actions of GABA at GABA-A receptors. Steroids containing negatively charged groups inhibit GABAergic neurotransmission. NMDA receptors are modulated, either positively or negatively, by steroids that contain negatively charged groups. Thus, understanding the actions of steroids at these receptors is important for understanding the clinical effects of the steroid class of anesthetics. The three specific aims of this project are focused on gaining new knowledge of the molecular details of the interactions of steroids with GABA-A and NMDA receptors. Synthetic chemistry will be performed to prepare novel analogues of anesthetic steroids for structure-activity relationships (SAR) studies. Electrophysiological, binding, and behavioral assayswill be used for evaluation of the compounds. Specific aim 1 addresses the importance of the steroid ring system for anesthetic steroid effects at GABA-A and NMDA receptors. In specific aim 2, anesthetic steroid analogues containing fluorescent groups will be prepared to: 1) investigate how steroids access their binding sites in the transmembrane domains of GABA-A receptors; and 2) investigate the entry and distribution of anesthetic steroids in brain cells. Specific aim 3 will investigate the molecular basis for the enantioselectivity of anesthetic steroid action at GABA-A receptors. The long term goals of this project are to use the methods of medicinal chemistry to obtain new pharmacological tools for investigationof the effects of steroids at GABA-A and NMDA receptors. Ultimately, this information could lead to the discovery of new anesthetic, anticonvulsant, anxiolytic and sedative hypnotic drugs.