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 全身麻醉剂。在中枢神经系统中，GABA-A 受体功能增强 抑制性神经传递和抑制 NMDA 受体功能会降低兴奋性 神经传递。麻醉类固醇增强 GABA 对 GABA-A 受体的作用。类固醇 含有负电荷的基团抑制 GABA 能神经传递。 NMDA 受体是 由含有带负电基团的类固醇进行正向或负向调节。因此， 了解类固醇对这些受体的作用对于了解其临床效果非常重要 类固醇类麻醉剂。 该项目的三个具体目标集中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。将进行合成化学 制备用于构效关系 (SAR) 研究的麻醉类固醇的新型类似物。 电生理学、结合和行为测定将用于评估化合物。 具体目标 1 强调类固醇环系统对于麻醉类固醇作用的重要性 GABA-A 和 NMDA 受体。具体目标2，含有荧光基团的麻醉类固醇类似物 将准备好：1）研究类固醇如何进入跨膜域中的结合位点 GABA-A受体； 2) 研究麻醉类固醇在脑细胞中的进入和分布。具体的 目标 3 将研究 GABA-A 麻醉类固醇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方法获得新的 研究类固醇对 GABA-A 和 NMDA 受体影响的药理学工具。最终， 这些信息可能有助于发现新的麻醉剂、抗惊厥剂、抗焦虑剂和镇静剂 安眠药。