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.
3-(4-[(3-Chlorophenyl)methoxy]phenyl)-5-[(methylamino)methyl]-2- oxazolidinone methanesulphonate (compound MD 780236) is a selective inhibitor of the B-form of monoamine oxidase. Inhibition involves an initial non-covalent interaction between enzyme and inhibitor followed by a time-dependent process resulting in irreversible inhibition. The initial, reversible, phase of inhibition was found to be competitive with respect to phenethylamine and 5-hydroxytryptamine, and a comparison of the Ki values indicated the affinity of the inhibitor for the B-form of the enzyme to be some 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 some 530-fold greater than that of the process leading to irreversible inhibition of the B-form of the enzyme.
D000818:Animals; D006861:Hydrogen Peroxide / Q000378:metabolism; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008297:Male; D008930:Mitochondria, Liver / Q000201:enzymology; D008954:Models, Biological; D008996:Monoamine Oxidase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D010080:Oxazoles / Q000378:metabolism / Q000494:pharmacology*; D023303:Oxazolidinones; D010084:Oxidation-Reduction; D010627:Phenethylamines / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism; D013997:Time Factors
D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; D010080:Oxazoles; D023303:Oxazolidinones; D010627:Phenethylamines; C029261:phenethylamine; D012701:Serotonin; C037871:MD 780236; D006861:Hydrogen Peroxide