Synthesis of Chiral 1-(2‘-Amino-2‘-carboxyethyl)-1,4-dihydro-6,7-quinoxaline-2,3-diones: α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionate Receptor Agonists and Antagonists
| Autor: | Gamal Shams, Guoping Sun, David M. Weinstein, Norman J. Uretsky, Duane D. Miller, Lane J. Wallace |
|---|---|
| Rok vydání: | 1996 |
| Předmět: | |
| Zdroj: | Journal of Medicinal Chemistry. 39:4430-4438 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm950632+ |
| Popis: | Recently discovered 6,7-disubstituted quinoxaline-2,3-diones, 1, have been found to antagonize specific binding and functional responses to both α-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 μM, 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 μM, respectively. Both enantiomers were agonists in a functional assay, with the S-isomer having an EC50 value... |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|