TRANSFORMATION OF HETEROCYCLIC REVERSIBLE MONOAMINE OXIDASE-B INACTIVATORS INTO IRREVERSIBLE INACTIVATORS BY N-METHYLATION

xy]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 derivative s of 1, as well as of the corresponding dihydrofuranone and pyrrolidin one, had been shown to be time-dependent, but reversible, inhibitors o f MAO-B. Here it is shown that the primary amine analogue of 1 is a ti me-dependent reversible inhibitor of MAO-B and that the secondary and tertiary amine analogues of the corresponding oxazolidinone, dihydrofu ranone, and pyrrolidinone are time-dependent irreversible inhibitors o f MAO-B. The reaction leading to the irreversible enzyme adduct format ion with 1 can be reversed by increasing the temperature. These result s are consistent with a stabilizing stereoelectronic effect on the enz yme adduct caused by N-methylation which hinders free rotation and pre vents the Sp3-orbital containing the nitrogen nonbonded electrons from being trans to the active site amino acid leaving group.