Synthesis of chiral 1-(2'-amino-2'-carboxyethyl)-1,4-dihydro-6,7-quinoxaline-2,3-diones: alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor agonists and antagonists.

Recently discovered 6,7-disubstituted quinoxaline-2,3-diones, 1, have been found to antagonize specific binding and functional responses to both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and kainic acid. Although a variety of studies have analyzed the activity of quinoxaline-2,3-diones with various substitutions at positions 6 and 7, there is little information regarding the effects of N-substitution. A racemic mixture of 1-(2'-amino-2'-carboxyethyl)-1,4-dihydroquinoxaline-2, 3-dione (QXAA, 2, R1 = R2 = H) has been synthesized from 1 (R1 = R2 = H). This compound inhibited specific [3H]AMPA binding but not [3H]kainate binding. IC50 values for QXAA, AMPA, and DNQX were 0.69, 0.012, and 0.74 microM, respectively. The R- and S-enantiomers were prepared by asymmetric synthesis. The S-isomer (2b) was 160-fold more potent in binding assays than the R-isomer (2d), with IC50 values of 0.23 and 38 microM, respectively. Both enantiomers were agonists in a functional assay, with the S-isomer having an EC50 value of 3 microM while that for the R-isomer was greater than 1 mM. Methyl substitutions at positions 6 and 7 (2a and 2c) resulted in antagonist compounds characterized by the S- and R-isomers being nearly equipotent, with IC50 values of 51 and 22 microM in the binding assay and EC50 values of 290 and 300 microM in the functional assay. AMPA had an EC50 value of 11 microM and DNQX an EC50 value of 30 microM in the functional assay. Analogs of quinoxalinediones with side chains other than an amino acid moiety on the nitrogen did not show good binding activities.