SYNTHESIS OF CHIRAL RBOXYETHYL)-1,4-DIHYDRO-6,7-QUINOXALINE-2,3-DIONES - PHA-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLEPROPIONATE RECEPTOR AGONISTS AND ANTAGONISTS
Gp. Sun et al., SYNTHESIS OF CHIRAL RBOXYETHYL)-1,4-DIHYDRO-6,7-QUINOXALINE-2,3-DIONES - PHA-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLEPROPIONATE RECEPTOR AGONISTS AND ANTAGONISTS, Journal of medicinal chemistry, 39(22), 1996, pp. 4430-4438
Recently discovered 6,7-disubstituted quinoxaline-2,3-diones, 1, have
been found to antagonize specific binding and functional responses to
both pha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and kai
nic 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 -2'-carboxyethyl)-1,4-dihydroquinoxaline-2,3-dio
ne (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, 0.01
2, 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 i
n 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 f
or the R-isomer was greater than 1 mM. Methyl substitutions at positio
ns 6 and 7 (2a and 2c) resulted in antagonist compounds characterized
by the S- and R-isomers being nearly equipotent, with IC50 values of 5
1 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 DN
QX an EC(50) value of 30 mu M in the funtional assay. Analogs of quino
xalinediones with side chains other than an amino acid moiety on the n
itrogen did not show good binding activities.