CHEMISTRY OF DRUG ACTION OF SOME MAO INHIBITORS

一些 MAO 抑制剂的药物作用化学

• 批准号: 3281670
• 负责人: RICHARD B SILVERMAN
• 金额: $ 8.35万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-04-01 至 1986-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3281670
• 关键词: MAO inhibitors; benzylamines; chemical models; cyclic amine; drug design /synthesis /production; electron spin resonance spectroscopy; enzyme substrate; free radicals; liver; mitochondria; oxidation; pharmacology; radiotracer

Monoamine oxidase (MAO) inhibitors are known to be important antidepressant and antihypertensive agents. Our initial studies indicate that N-cyclopropyl-N-arylalkyl amines, a class of potent MAO inhibitors, are suicide inactivators of MAO. Experiments are designed to confirm the mechanism proposed for this irreversible inactivation. This includes gaining insight into the chemical mechanism of oxidation of monoamines catalyzed by MAO. In addition to enzymatic reactions using labeled substrates and inhibitors, non-enzymatic model reactions will be employed. The chemistry of oxidation of reversible inhibitors also will be investigate to assist in understanding the mechanisms of inactivation of the N-cyclopropyl-N-arylakyl amines and the oxidation pathway catalyzed by MAO. A compound will be tested as a new inactivator of MAO, designed to covalently attach to an active site residue other than flavin via a suicide inactivator mechanism. Also, a new class of potential MAO inactivators will be tested.

已知单胺氧化酶 (MAO) 抑制剂是重要的抗抑郁药 抗高血压药。 我们的初步研究表明 N-环丙基-N-芳基烷基胺是一类有效的 MAO 抑制剂，具有自杀性 MAO 灭活剂。 实验旨在证实所提出的机制 对于这种不可逆转的失活。 这包括深入了解 MAO催化单胺氧化的化学机理。 此外 使用标记底物和抑制剂的酶促反应，非酶促模型 将采用反应。 可逆抑制剂的氧化化学 还将进行调查以帮助了解其机制 N-环丙基-N-芳烷基胺的失活和氧化途径 由MAO催化。 一种化合物将作为新的 MAO 灭活剂进行测试， 设计用于通过共价键连接到黄素以外的活性位点残基上 自杀灭活剂机制。 此外，一类新的潜在 MAO 灭活剂 将受到测试。