Synthesis, chiral resolution and pharmacological evaluation of a 2,3-benzodiazepine-derived noncompetitive AMPA receptor antagonist.

The resolution of 1-(4-aminophenyl)-3,5-dihydro-3-N-ethylcarbamoyl-5-methyl-7,8-methylenedioxy-4H-2,3-benzodiazepin-4-one (R,S)-(+/-)-5 by chiral HPLC and assignment of the absolute configuration of the two enantiomers was carried out. Compound (R,S)-(+/-)-5 and its enantiomers were tested in a binding assay to evaluate their affinity for AMPA receptors. Enantiomer (S)-(-)-5 appears to be more potent than its optical antipode (R)-(+)-5. In a primary culture of rat cerebellar granule cells, which express AMPA receptors, (R,S)-(+/-)-5 and (S)-(-)-5 inhibited kainate- induced [Ca(2+)](i) increase, thus confirming the antagonism at the AMPA receptor.