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, R(1) = R(2) = H) has been synthesized from 1 (R(1) = R(2) = H). This compound inhibited specific [H-3]AMPA binding but not [H-3]kainate binding. IC50 values for QXAA, AMPA, and DNQX were 0.69, 0.012, and 0.74 mu M, 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 mu M, respectively. Both enantiomers were agonists in a functional assay, with the S-isomer having an EC(50) value of 3 mu M 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 mu M in the binding assay and EC(50) values of 290 and 300 mu M in the functional assay. AMPA had an EC(50) value of 11 mu M and DNQX an EC(50) value of 30 mu M in the funtional assay. Analogs of quinoxalinediones with side chains other than an amino acid moiety on the nitrogen did not show good binding activities.