Transformation of heterocyclic reversible monoamine oxidase-B inactivators into irreversible inactivators by N-methylation.
3-[4-[(3-Chlorophenyl)methoxy]phenyl]-5-[(methylamino)methyl]- 2-oxazolidinone (1) is a secondary amine known to be a potent time-dependent irreversible inactivator of monoamine oxidase B (MAO-B). The primary amine analogues of derivatives of 1, as well as of the corresponding dihydrofuranone and pyrrolidinone, had been shown to be time-dependent, but reversible, inhibitors of MAO-B. Here it is shown that the primary amine analogue of 1 is a time-dependent reversible inhibitor of MAO-B and that the secondary and tertiary amine analogues of the corresponding oxazolidinone, dihydrofuranone, and pyrrolidinone are time-dependent irreversible inhibitors of MAO-B. The reaction leading to the irreversible enzyme adduct formation with 1 can be reversed by increasing the temperature. These results are consistent with a stabilizing stereoelectronic effect on the enzyme adduct caused by N-methylation which hinders free rotation and prevents the sp3-orbital containing the nitrogen nonbonded electrons from being trans to the active site amino acid leaving group.
Ding
C Z
CZ
Department of Chemistry, Northwestern University, Evanston, Illinois 60208-3113.
Silverman
R B
RB
D000818:Animals; D001665:Binding Sites; D002417:Cattle; D004789:Enzyme Activation / Q000187:drug effects; D004793:Enzyme Reactivators; D005663:Furans / Q000138:chemical synthesis / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008745:Methylation; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D010080:Oxazoles / Q000737:chemistry* / Q000494:pharmacology; D023303:Oxazolidinones; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship
D004793:Enzyme Reactivators; D005663:Furans; D008996:Monoamine Oxidase Inhibitors; D010080:Oxazoles; D023303:Oxazolidinones; D011760:Pyrrolidinones; C037871:MD 780236; D008995:Monoamine Oxidase