STRUCTURE/ACTIVITY STUDIES OF NEUROSTEROID ANALOGUES

神经类固醇类似物的结构/活性研究

• 批准号: 8118826
• 负责人: DOUGLAS F COVEY
• 金额: $ 36.69万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8118826
• 关键词: Address; Allopregnanolone; Aminobutyric Acids; Androgens; Androsterone; Anesthesia procedures; Anesthetics; Anti-Anxiety Agents; Anticonvulsants; Behavioral; Benzodiazepines; Binding; Binding Sites; Cell membrane; Charge; Chloride Ion; Chlorides; D Aspartate; Etiocholanolone; Evaluation; Future; GABA Modulators; General anesthetic drugs; Glutamates; Goals; Heterogeneity; Hydrogen Bonding; Ion Channel; Ketamine; Ketones; Knowledge; Lead; Light; Location; Mediating; Membrane Lipids; Methods; Modeling; Molecular; Neuraxis; Neurons; Nitrous Oxide; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Positioning Attribute; Pregnanolone; Preparation; Principal Investigator; Process; Relative (related person); Shapes; Steroids; Structure; Structure-Activity Relationship; Synthesis Chemistry; System; Transmembrane Domain; Work; absorption; analog; aqueous; aspartate receptor; base; brain cell; clinical effect; design; enantiomer; gamma-Aminobutyric Acid; hypnotic; neurosteroids; neurotransmission; novel; programs; receptor; receptor function; sedative; steroid analog; steroid sulfate; tool

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.

项目1 GABA-A或NMDA受体的调节是大多数临床使用的麻醉作用的基础 一般麻醉药。在中枢神经系统中，GABA-A受体功能的增强增加 抑制性神经传递和NMDA受体功能的抑制可降低兴奋性 神经传递。麻醉类固醇增强了GABA对GABA-A受体的作用。类固醇 包含带负电荷的组抑制GABA能神经传递。 NMDA受体是 由包含带负电荷组的类固醇进行正面或负面调节。因此， 了解类固醇对这些受体的作用对于理解的临床影响很重要 麻醉药类固醇类。 该项目的三个具体目的侧重于获得有关分子细节的新知识 类固醇与GABA-A和NMDA受体的相互作用。合成化学将进行 为结构活性关系（SAR）研究准备麻醉类固醇的新型类似物。 电生理，结合和行为测定将用于评估化合物。 具体目标1解决了类固醇环系统对麻醉类固醇效应的重要性 GABA-A和NMDA受体。在特定的目标2中，含有荧光基团的麻醉类固醇类似物 将准备以下：1）研究类固醇如何在跨膜结构域中访问其结合位点 GABA-A受体； 2）研究麻醉类固醇在脑细胞中的进入和分布。具体的 AIM 3将研究麻醉类固醇在GABA-A的映选择性的分子基础 受体。 该项目的长期目标是使用药物化学方法来获得新 研究类固醇对GABA-A和NMDA受体的影响的药理工具。最终， 这些信息可能导致发现新的麻醉，抗惊厥药，抗焦虑和镇静剂 催眠药。