CHEMISTRY OF DRUG ACTION OF SOME MAO INHIBITORS

一些 MAO 抑制剂的药物作用化学

• 批准号: 3281667
• 负责人: RICHARD B SILVERMAN
• 金额: $ 12.98万
• 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 1990-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3281667
• 关键词: MAO inhibitors; antidepressants; benzylamines; chemical binding; chemical models; cyclic amine; drug design /synthesis /production; drug metabolism; electron spin resonance spectroscopy; enzyme substrate; free radicals; liver; mitochondria; neurotransmitters; oxidation; radiotracer

Monoamine oxidase (MAO) is one of the enzymes responsible for the catabolism of biogenic amines. Compounds that inhibit MAO exhibit antidepressant activity; tranylcypromine, for example, is a potent cyclopropylamine-containing antidepressant drug that inactivates MAO. The mechanisms of MAO-catalyzed amine oxidation and the mechanism of MAO inactivation by the cyclopropylamine-containing inactivators are unknown. Preliminary evidence from our lab indicates that a radical mechanism is involved. The research described in this proposal involves several different aspects of the mechanism of action and inactivation of MAO. New inactivators of MAO are designed and will be synthesized. Their mechanisms of inactivation will be studied using homogeneous MAO and radioactive labels in the inactivators. The mechanisms of other known inactivators of MAO also will be investigated. For those inactivators that become attached to active site amino acid residues, it will be determined which amino acid(s) is(are) involved in order to map the active site. Several approaches will be taken to gain further evidence for the generation of radicals during reactions catalyzed by MAO. Some approaches involve studies of MAO-catalyzed reaction products which may support radical chemistry; other work involves electron spin resonance spectroscopy of intermediates or radical-trapped products. The stereospecificity of substrate and inactivator reactions catalyzed by MAO will be ascertained so that this information may be utilized in the design of more specific inhibitors. The results of these studies will be important to the understanding of how MAO catalyzes biogenic amine degradation and to the development of new antidepressant agents.

单胺氧化酶（MAO）是负责代谢的酶之一。 生物胺的分解代谢。 抑制MAO的化合物表现出 抗抑郁活性;例如，反苯环丙胺是一种有效的 使单胺氧化酶失活的含环丙胺的抗抑郁药。 的 单胺氧化酶催化胺氧化反应机理及单胺氧化酶的作用机理 通过含环丙胺的灭活剂的灭活是未知的。 我们实验室的初步证据表明， 涉案 本提案中所述的研究涉及几个方面， 不同方面的作用机制和失活的单胺氧化酶。 新 设计并合成了单胺氧化酶的钝化剂。 作用机理 将使用均相MAO和放射性 灭活剂中的标签。 其他已知的灭活剂的机制， 毛泽东也将接受调查。 对于那些附着在 活性位点氨基酸残基，将确定哪个氨基酸 酸参与以绘制活性位点。 几 将采取措施，以获得进一步的证据， 自由基在由MAO催化的反应期间。 某些方法涉及 MAO催化的反应产物可能支持自由基的研究 化学;其他工作涉及电子自旋共振光谱的 中间体或自由基捕获产物。 的立体专一性 底物和灭活剂反应的催化MAO将被确定， 这些信息可以用于设计更具体的 抑制剂的 这些研究的结果将是重要的 了解MAO是如何催化生物胺降解的， 开发新的抗抑郁药。