CHEMISTRY OF DRUG ACTION OF SOME MAO INHIBITORS

一些 MAO 抑制剂的药物作用化学

• 批准号: 3281674
• 负责人: RICHARD B SILVERMAN
• 金额: $ 27.88万
• 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/3281674
• 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 radicals; 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）是负责代谢的酶之一。 各种生物胺如去甲肾上腺素，血清素， 和多巴胺。 在慢性抑郁症患者中发现， 各种生物胺的浓度降低。 因此，委员会认为， 抑制或抑制β-MAO的化合物显示抗抑郁活性。 本研究的长期目标是阐明单胺氧化酶的机制 催化各种氧化反应，以确定化学 参与各种灭活剂对MAO的灭活， 确定了MAO的活性中心结构。 本项目期间的具体目标是调查异常 通过MAO催化的反应，细化自由基氧化机理， 设计新型单胺氧化酶灭活剂，研究单胺氧化酶的灭活机理 通过已知的MAO灭活剂以及通过新设计的灭活剂， 鉴定MAO活性位点残基和肽作为第一步 活性中心结构的阐明，并研究 各种MAO反应的立体化学。 不寻常的反应 感兴趣的包括1-苯基环丁胺的MAO催化氧化和 通过有机溶剂改变MAO催化的反应。 进一步 涉及自由基的证据将通过具有以下结构的化合物获得： 内置的激进分子陷阱 提出了化合物来区分 电子转移-质子转移机理 电子转移-氢原子转移机理。 10个新类别 恶唑烷酮灭活单胺氧化酶的潜在机制， （氨基烷基）三甲基硅烷，（氨基烷基）三甲基锗烷， 米拉塞米，和反苯环丙胺将研究与使用一个 这些类别的每一种的各种放射性标记的类似物 灭活剂。 活性位点残基和肽标记的各种 环丙胺，由（氨乙基）三甲基硅烷，由米拉塞米，和由 将测定N-（2-氨乙基）-4-氯苯甲酰胺。 的立体化学 仲胺的氧化和MAO钝化剂将是 测定 这些研究的结果应该是重要的， 了解MAO如何催化各种反应以及如何不同 化合物的种类