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 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.