The inhibition of cerebral glutamine synthetase by structural analogs of the convulsant dl-methionine sulfoximine.

GLUTAMINE synthetase [L-glutamate-ammonia ligase (ADP)] (EC 6.3.1.2) of rat cerebral cortex may be readily inhibited by the convulsant agent dl-methionine-di-sulfoximine (MSO), both in vitro and in vivo. 1, 8 Although in vitro this inhibition is readily reversible by excess substrate, L-glutamate, the inhibition in vivo appears to reflect a nonreversible interaction of the convulsant drug with the enzyme protein, which becomes maximal at the time the animal experiences the first seizure episode and which, as has been suggested, 8 possibly involves cunformatiunal changes in the enzyme molecule. As neither methionine sulfoxide nor methionine sulfone could be shown to inhibit in vivo the cerebral glutamine synthetase-glutamine transferas¢ system, 8 the examination of the contribution of the sulfoximinomoiety of MSO as a determining factor conferring specificity to the drug-enzyme interaction became of interest. In this communication we wish to report results of experiments in which four structural analogs of MSO, three S-alkyl-homocysteine sulfoximines, and one S-alkyl cysteine sulfoximine were evaluated as inhibitors of cerebral glutamine synthetase in vitro.