CHEMISTRY OF DRUG ACTION OF SOME MAO INHIBITORS

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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.