NEW METHODS FOR SYNTHESIS OF NEUROLOGICAL AGENTS

合成神经药物的新方法

• 批准号: 2262419
• 负责人: LARRY E. OVERMAN
• 金额: $ 31.82万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-06-01 至 1999-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2262419
• 关键词: NMDA receptors; alkaloids; chemical structure function; chemical synthesis; cyclization; drug design /synthesis /production; heterocyclic compounds; method development; molecular rearrangement; muscarinic receptor; neuromuscular blocking agents; neuropharmacologic agent; nucleoside analog; opiate alkaloid; sesquiterpenes; stereochemistry; strychnine

This application process to develop new organic synthesis methodology that will allow compounds with potential biological (primarily neurological) activity to be prepared in sufficient quantities for detailed biological evaluations. Exploratory studies of new ring forming reactions, complex molecule total syntheses, and collaborative pharmacological studies of selected total synthesis targets are proposed. The primary health significance of the research outlined in this application is the potentially powerful new ring construction methodology to be developed. It is not our aim to discover new drugs, but rather to define versatile new organic synthesis tools to enable such discoveries in the future. A secondary health significance of the research proposed in this application derives from the biological activity (primarily neurological) of our synthesis targets. The studies proposed for the NS-12389-18-22 project years focus on developing "pinacol-terminated" cationic cyclizations (discovered during the current NS project period) for the efficient synthesis of a variety of complex heterocycles and carbocycles. Our successful program to exploit the "aza-Cope-Mannich" reaction (discovered under the auspices of NS-12389) as the key element of a broadly applicable strategy for alkaloid synthesis will also be continued. Total synthesis targets include the Strychnos alkaloids (plus minus)-akuammicine, (plus minus)-norfluorocurarine and (-)- strychnine; the methanomorphanthridine alkaloids (+)-megellaninone and the polyether marine sesquiterpene natural product (-)-kumausallene. A series of branched chain C-nucleoside analogs and potential centrally acting muscarinic agonists will be prepared and biologically evaluated. Muscarinic agonists that effect muscarinic receptors in the cortex are of potential use in treating cognitive disorders such as Alzheimer's disease. Strychnos alkaloids exhibit powerful neurological activities and members of this group are among the most paralytic neuromuscular blocking agents known today. Our collaborative studies of new NMDA receptor antagonists (prepared during the current NS grant period) will also be continued. Such antagonists are of potential use in the treatment of several neurodegenerative diseases.

这种申请过程开发了新的有机合成方法论 将允许具有潜在生物学（主要是神经系统）的化合物 以足够数量准备的活动以详细生物学 评估。 新环反应，复杂的探索性研究 分子总合成和协作药理学研究 提出了选定的总合成目标。 主要健康 本应用程序中概述的研究的意义是 可能要开发的潜在强大的新环构建方法。 它 不是我们发现新药的目的，而是定义多功能新药 有机综合工具将来能够在未来进行此类发现。 一个 本应用程序提出的研究的二级健康意义 源自我们的生物学活性（主要是神经学） 合成目标。 针对NS-12389-18-22项目年的研究重点是 开发“ Pinacol终止”的阳离子循环（在 当前的NS项目时期）有效合成各种 复杂的杂环和碳纤维。 我们成功利用的计划 “ Aza-Cope-Mannich”反应（以NS-12389的主持人发现） 作为生物碱合成的广泛适用策略的关键要素 也将继续。 总合成目标包括Strychnos 生物碱（加上负） - akuammicine，（加上负） - norfluorocurarine和（ - ） - 斯特里宁;甲烷类胰素生物碱（+） - 杂醇酮和 聚乙烯海洋倍半萜天然产物（ - ） - 库马列烯。 系列 分支链C-核苷类似物和潜在作用 毒蕈碱激动剂将得到准备并通过生物学评估。 在皮质中影响毒蕈碱受体的毒蕈碱激动剂是 治疗认知障碍（例如阿尔茨海默氏病）的潜在用途。 Strychnos生物碱表现出强大的神经活动和成员 该组是已知的最瘫痪的神经肌肉阻断剂 今天。 我们对新NMDA受体拮抗剂的合作研究 （在当前NS赠款期间准备）也将继续。 这样的 拮抗剂在治疗几个 神经退行性疾病。