Reference

Asymmetric Synthesis of 1-(2'-Amino-2'-carboxyethyl)-1,4-dihydro-6,7-quinoxaline-2,3-diones: a-Amino-3-hydroxy-5-methyl-4-isoxazolepropionate Receptor Agonists and Antagonists

Asymmetric Synthesis of 1-(2'-Amino-2'-carboxyethyl)-1,4-dihydro-6,7-quinoxaline-2,3-diones: a-Amino-3-hydroxy-5-methyl-4-isoxazolepropionate Receptor Agonists and Antagonists. Sun, Guoping; Uretsky, Norman J.; Wallace, Lane J.; Shams, Gamal; Weinstein, David M.; Miller, Duane D. (Department of Pharmaceutical Sciences, University of Tennessee, Memphis, TN 38163, USA). Journal of Medicinal Chemistry, 39(22), 4430-4438 (English) 1996 American Chemical Society. CODEN: JMCMAR. ISSN: 0022-2623. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Section cross-reference(s): 28 Recently discovered 6,7-disubstituted quinoxaline-2,3-diones have been found to antagonize specific binding and functional responses to both a-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.There are some reagents with their cas registry numbers 126330-77-6 and 6368-20-3 are used in this study. A racemic mixt. of 1-(2'-amino-2'-carboxyethyl)-1,4-dihydroquinoxaline-2,3-dione (QXAA, I, R1 = R2 = H) has been synthesized. This compd. 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 mM, resp. The R- and S-enantiomers were prepd. by asym. synthesis. The S-isomer was 160-fold more potent in binding assays than the R-isomer, with IC50 values of 0.23 and 38 mM, resp. Both enantiomers were agonists in a functional assay, with the S-isomer having an EC50 value of 3 mM while that for the R-isomer was greater than 1 mM. Me substitutions at positions 6 and 7 resulted in antagonist compds. characterized by the S- and R-isomers being nearly equipotent, with IC50 values of 51 and 22 mM in the binding assay and EC50 values of 290 and 300 mM in the functional assay. AMPA had an EC50 value of 11 mM and DNQX an EC50 value of 30 mM 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. .