CHEMISTRY OF DRUG ACTION OF SOME MAO INHIBITORS

单胺氧化酶(MAO)是一种负责 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，三羟环丙胺是一种有效的 含有环丙胺的抗抑郁药，可使MAO失活。这个 MAO催化的胺氧化机理及MAO的作用机理 含有环丙胺的灭活剂的灭活作用尚不清楚。 我们实验室的初步证据表明，一种激进的机制是 牵涉其中。这项提案中描述的研究涉及几个 MAO的作用和失活机制的不同方面。新的 设计并合成了MAO的灭活剂。他们的机制 将使用均相MAO和放射性来研究失活 灭活剂上的标签。其他已知的灭活剂的作用机制 毛也将接受调查。对于那些被附着的灭活剂 对于活性部位的氨基酸残基，则要确定哪些氨基酸 为了绘制活性部位图，涉及到酸(S)。几个 将采取各种方法来获得进一步的证据，以证明 在MAO催化的反应中产生的自由基。一些方法涉及 可能支持自由基的MAO催化反应产物的研究 化学；其他工作涉及电子自旋共振波谱 中间体或自由基陷阱产品。的立体专一性 MAO催化的底物和失活剂反应将被确定为 这一信息可能被用于设计更具体的 抑制剂。这些研究的结果将对 对MAO如何催化生物胺降解的理解以及对 新的抗抑郁药物的开发。

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.