CHEMISTRY OF DRUG ACTION OF SOME MAO INHIBITORS

一些 MAO 抑制剂的药物作用化学

• 批准号: 2176669
• 负责人: RICHARD B SILVERMAN
• 金额: $ 27.35万
• 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 1995-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2176669
• 关键词: MAO inhibitors; acetamides; antidepressants; benzylamines; cyclic amine; drug design /synthesis /production; drug metabolism; electron spin resonance spectroscopy; electron transport; enzyme mechanism; enzyme structure; enzyme substrate; free radical oxygen; germanium; high performance liquid chromatography; oxidation; radiotracer; silanes; stereochemistry

Monoamine oxidase (MAO) is one of the enzymes responsible for the catabolism of various biogenic amines such as norepinephrine, serotonin, and dopamine. It has been shown in chronically-depressed individuals that the concentrations of various biogenic amines is diminished. Consequently, compounds that inhibit or inactivate MAO exhibit antidepressant activity. The long-term goals of this research are to elucidate the mechanism for MAO catalysis of a variety of oxidation reactions, to determine the chemistry involved in the inactivation of MAO by various inactivators, and to determine the active site structure of MAO. The specific aims for this project period are to investigate unusual reactions catalyzed by MAO, to refine the radical oxidation mechanism, to design new inactivators of MAO, to study mechanisms of inactivation of MAO by known MAO inactivators as well as by newly-designed inactivators, to identify active site residues and peptides of MAO as a first step toward the elucidation of the active site structure, and to investigate the stereochemistry of various MAO reactions. The unusual reactions of interest include MAO-catalyzed oxidation of 1-phenylcyclobutylamine and the alteration of MAO-catalyzed reactions by organic solvents. Further evidence for involvement of radicals will be obtained with compounds having built-in radical traps. Compounds are proposed to differentiate an electron transfer-proton transfer electron transfer mechanism from an electron transfer-hydrogen atom transfer mechanism. Ten new classes of potential MAO mechanisms of inactivation of MAO by oxazolidinones, by (aminoalkyl) trimethylsilanes, by (aminoalkyl) trimethylgermanes, by milacemide, and by tranylcypromine will be studied with the use of a variety of radioactively-labeled analogues of each of these classes of inactivators. Active-site residues and peptides labeled by various cyclopropylamines, by (aminoethyl) trimethylsilane, by milacemide, and by N-(2-aminoethyl)-4-chlorobenzamide will be determined. The stereochemistry of oxidation of secondary amines and of MAO inactivators will be determined. The results of these studies should be important to the understanding of how MAO catalyzes a variety of reactions and how different classes of compounds inactivate MAO.

单胺氧化酶(MAO)是一种负责 各种生物胺的分解代谢，如去甲肾上腺素、5-羟色胺、 和多巴胺。在患有慢性抑郁症的人身上已经显示出 各种生物胺的浓度都降低了。因此， 抑制或灭活MAO的化合物显示出抗抑郁活性。 本研究的长期目标是阐明MAO的发病机制。 催化各种氧化反应，测定化学性质 参与了各种失活剂对MAO的失活，并 确定了MAO的活性中心结构。 此项目期间的具体目标是调查异常情况 由MAO催化的反应，以完善自由基氧化机制， 设计新型MAO失活剂，研究MAO失活机理 已知的MAO灭活剂以及新设计的灭活剂，以 鉴定MAO的活性部位残基和多肽作为迈向 阐明了活性中心的结构，并对其进行了研究 各种MAO反应的立体化学。他的反常反应 感兴趣的包括MAO催化氧化1-苯基环丁胺和 有机溶剂对MAO催化反应的影响。进一步 有关自由基参与的证据将通过具有以下成分的化合物获得 内置激进陷阱。化合物的提出是为了区分 电子转移-质子转移电子转移机理的研究 电子转移-氢原子转移机理。十个新班级 恶唑烷酮类化合物灭活MAO的潜在MAO机制 (氨基烷基)三甲基硅烷 Milacemide和三羟环丙胺将通过使用一种 这些类别中每一类的放射性标记类似物的种类 灭活剂。不同分子标记的活性中心残基和多肽 环丙胺、(氨乙基)三甲基硅烷、Milacemide和 测定N-(2-氨基乙基)-4-氯苯甲酰胺。立体化学 仲胺的氧化和MAO的灭活剂将是 下定决心。这些研究的结果应该对 了解MAO如何催化各种反应以及如何不同 各类化合物使MAO失活。