144435-09-6Relevant articles and documents
Novel α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor antagonists: Synthesis and structure-activity relationships of 6-(1H- imidazol-1-yl)-7-nitro-2,3(1H,4H)-pyrido[2,3-b]pyrazinedione and related compounds
Ohmori,Kubota,Shimizu-Sasamata,Okada,Sakamoto
, p. 1331 - 1338 (1996)
We have synthesized and evaluated azaquinoxalinediones 3a-c for their activity in inhibiting [3H]AMPA binding from rat whole brain. It was found that the azaquinoxalinedione nucleus functions as a bioisostere for quinoxalinedione in AMPA receptor binding. The detailed structure-activity relationships of 6- and/or 7-substituted 2,3(1H,4H)-pyrido[2,3- b]pyrazinedione derivatives 4, 7-10, 13, 15, and 16 showed some differences in comparison with those of the corresponding substituted quinoxalinediones, including 6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione (1) (YM90K). The X-ray study exhibited that conformation of the 7-nitro group of 1 · HCl was nearly coplanar with the quinoxaline ring, whereas the 6- imidazol1-yl group was rotated with respect to the aromatic ring. From the glycine site on NMDA receptor binding study, it is indicated that bulkiness of 6-substituents on pyridopyrazinediones may be responsible for the selectivity against the glycine site. Among the series of azaquinoxalinediones, 6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-pyrido[2,3- b]pyrazinedione (8c) exhibited a combination of the best affinity to the AMPA receptors with a K(i) value of 0.14 μM and selectivity against the glycine site (no affinity at 10 μM). In vivo, 8c also protected against sound- induced seizure in DBA/2 mice (minimum effective dose, 10 mg/kg ip).
5-(N-oxyaza)-7-substituted-1,4-dihydroquinoxaline-2,3-diones: Novel, systemically active and broad spectrum antagonists for NMDA/glycine, AMPA, and kainate receptors
Cai, Sui Xiong,Huang, Jin-Cheng,Espitia, Stephen A.,Tran, Minhtam,Ilyin, Victor I.,Hawkinson, Jon E.,Woodward, Richard M.,Weber, Eckard,Keana, John F.W.
, p. 3679 - 3686 (2007/10/03)
A group of 5-aza-7-substituted-1,4-dihydroquinoxaline-2,3-diones (QXs) and the corresponding 5-(N. oxyaza)-7-substituted QXs were prepared and evaluated as antagonists of ionotropic glutamate receptors. The in vitro potency of these QXs was determined by inhibition of [3H]-5,7- dichlorokynurenic acid ([3H]DCKA) binding to N-methyl-D-aspartate (NMDA)/glycine receptors, [3H]-(S)-α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid ([3H]AMPA) binding to AMPA receptors, and [3H]kainate ([3H]KA) binding to KA receptors in rat brain membranes. 5-(N- Oxyaza)-QXs 12a-e all have low micromolar or submicromolar potency for NMDA/glycine receptors and low micromolar potencies for AMPA and KA receptors. QXs 12a-e display 2-12-fold selectivity for NMDA/glycine receptors compared to AMPA receptors, and ~2-fold difference between AMPA and KA potency. In contrast to other QXs that either show high selectivity for NMDA (such as ACEA 1021) or AMPA (such as NBQX) receptors, these molecules are broad spectrum antagonists of ionotropic glutamate receptors. 7-Nitro-5-(N- axyaza)-QX (12e) is the most potent inhibitor among 12a-e, having IC50 values of 0.69, 1.3, and 2.4 μM at NMDA, AMPA, and KA receptors, respectively. In functional assays on glutamate receptors expressed in oocytes by rat cerebral cortex poly(A+) RNA, 7-chloro-5-(N-oxyaza)-QX (12a) and 7-nitro-5(N-oxyaza)-QX (12e) have K(b) values of 0.63 and 0.31 μM for NMDA/glycine receptors, and are 6- and 4-fold selective for NMDA over AMPA receptors, respectively. 5-(N-Oxyaza)-7-substituted-QXs 12a-e all have surprisingly high in vivo potency as anticonvulsants in a mouse maximal electroshock-induced seizure (MES) model. 7-Chloro-5-(N-oxyaza)-QX (12a), 7- bromo-5-(N-oxyaza)-QX (12b), and 7-methyl-5-(N-oxyaza)-QX (12c) have ED50 values of 0.82, 0.87, and 0.97 mg/kg iv, respectively. The high in vivo potency of QXs 12a-e is particularly surprising given their low log P values (~ -2.7). Separate studies indicate that QXs 12a and 12e are also active in vive as neuroprotectants and also have antinociceptive activity in animal pain models. In terms of in vivo activity, these 5-(N-oxyaza)-7-substituted- QXs are among the most potent broad spectrum ionotropic glutamate antagonists reported.
