The enzyme-activated irreversible inhibition of type-B monoamine oxidase by 3-{4-[(3-chlorophenyl)methoxy]phenyl}-5-[(methylamino) methyl]-2-oxazolidinone methanesulphonate (compound MD 780236) and the enzyme-catalysed oxidation of this compound as competing reactions

Abstract

3-{4-[(3-Chlorophenyl)methoxy]phenyl}-5-[(methylamino)methyl]-2-oxazolidinone methanesulfonate (compound MD 780236) is a selective inhibitor of the B-form of [rat liver] monoamine oxidase. Inhibition involves an initial noncovalent interaction between enzyme and inhibitor followed by a time-dependent process resulting in irreversible inhibition. The initial, reversible, phase of inhibition was competitive with respect to phenethylamine and 5-hydroxytryptamine, and a comparison of the K1 values indicated the affinity of the inhibitor for the B-form of the enzyme to be 7-fold greater than its affinity for the A-form. This selectivity was considerably enhanced by preincubation of the enzyme and inhibitor. Time courses showed that complete inhibition was not achieved under conditions where the inhibitor concentration was over 100-fold greater than that of the enzyme. Assay of the activity of monoamine oxidase by determining the release of hydrogen peroxide fluorometrically showed compound MD 780236 to be a substrate for as well as an inhibitor of monoamine oxidase, and kinetic analysis revealed that the rate of product formation was 530-fold greater than that of the process leading to irreversible inhibition of the B-form of the enzyme.