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

Guoping Sun, Norman J. Uretsky, Lane J. Wallace, Gamal Shams, David M. Weinstein, Duane Miller

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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 of 3 μM 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 μM in the binding assay and EC50 values of 290 and 300 μM in the functional assay. AMPA had an EC50 value of 11 μM and DNQX an EC50 value of 30 μM 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.

Original languageEnglish (US)
Pages (from-to)4430-4438
Number of pages9
JournalJournal of Medicinal Chemistry
Volume39
Issue number22
DOIs
StatePublished - Oct 23 1996

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Quinoxalines
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Inhibitory Concentration 50
Kainic Acid
Nitrogen
Amino Acids
FG 9041

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

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. / Sun, Guoping; Uretsky, Norman J.; Wallace, Lane J.; Shams, Gamal; Weinstein, David M.; Miller, Duane.

In: Journal of Medicinal Chemistry, Vol. 39, No. 22, 23.10.1996, p. 4430-4438.

Research output: Contribution to journalArticle

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title = "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",
abstract = "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 of 3 μM 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 μM in the binding assay and EC50 values of 290 and 300 μM in the functional assay. AMPA had an EC50 value of 11 μM and DNQX an EC50 value of 30 μM 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.",
author = "Guoping Sun and Uretsky, {Norman J.} and Wallace, {Lane J.} and Gamal Shams and Weinstein, {David M.} and Duane Miller",
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AU - Sun, Guoping

AU - Uretsky, Norman J.

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AU - Shams, Gamal

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