CHEMISTRY OF DRUG ACTION OF SOME MAO INHIBITORS

一些 MAO 抑制剂的药物作用化学

• 批准号: 3281676
• 负责人: RICHARD B SILVERMAN
• 金额: $ 29.47万
• 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/3281676
• 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) 是负责代谢的酶之一 各种生物胺的分解代谢，例如去甲肾上腺素、血清素、 和多巴胺。 研究表明，长期抑郁的人 各种生物胺的浓度降低。 最后， 抑制或灭活 MAO 的化合物具有抗抑郁活性。 本研究的长期目标是阐明 MAO 的机制 催化多种氧化反应，确定化学性质 参与各种灭活剂对 MAO 的灭活，并 确定 MAO 的活性位点结构。 本项目期间的具体目标是调查异常情况 MAO催化的反应，完善自由基氧化机制， 设计新的MAO失活剂，研究MAO失活机制 通过已知的 MAO 灭活剂以及新设计的灭活剂， 鉴定 MAO 的活性位点残基和肽，作为迈向这一目标的第一步 阐明活性位点结构，并研究 各种 MAO 反应的立体化学。 的异常反应 兴趣包括 MAO 催化的 1-苯基环丁胺的氧化和 有机溶剂改变 MAO 催化反应。 更远 自由基参与的证据将通过具有以下特征的化合物获得： 内置激进陷阱。 建议使用化合物来区分 电子转移-质子转移 电子转移机制 电子转移-氢原子转移机制。 十个新班级 恶唑烷酮类使 MAO 失活的潜在 MAO 机制 (氨基烷基)三甲基硅烷，由(氨基烷基)三甲基锗烷，由 米拉塞米和反苯环丙明将使用 这些类别中的每一类都有各种放射性标记的类似物 灭活剂。 活性位点残基和肽被各种标记 环丙胺、(氨基乙基)三甲基硅烷、米拉酰胺和 将测定N-(2-氨基乙基)-4-氯苯甲酰胺。 立体化学 仲胺和 MAO 灭活剂的氧化将 决定。 这些研究的结果应该对 了解 MAO 如何催化各种反应以及有何不同 各类化合物可使 MAO 失活。