Synthesis, chiral resolution and enantiopharmacology of a potent 2,3-benzodiazepine as noncompetitive AMPA receptor antagonist

This paper describes the synthesis of racemic 3,5-dihydro-5-methyl-7,8-methylenedioxy-4H-2,3-benzodiazepin- 4-one (()-5, attempted stereoselective synthesis of its enantiomers, chiral HPLC resolution of the racemate, and assignment of the absolute configuration. Enantiomer (5S)-(-)-5 is provided with an in vivo anticonvulsant activity 8 times higher than its enantiomer (5R)-(+)-5. This result is confirmed in the in vitro test by the ability to inhibit the kainate-induced increase of the [Ca2+]i in a primary culture of rat cerebellar granule cells which express R-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. Binding affinity of compound (()-5 at the AMPA and N-methyl-D-aspartic acid (NMDA) receptors was also evaluated.