Abstract:
: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, 7-1-, 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-imidazol-1-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 AMPA receptors with a Ki value of 0.14 microM and selectivity against the glycine site (no affinity at 10 microM). In vivo, 8c also protected against sound-induced seizure in DBA/2 mice (minimum effective dose, 10 mg/kg ip).
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Ohmori J,Kubota H,Shimizu-Sasamata M,Okada M,Sakamoto Sdoi
10.1021/jm950304+subject
Has Abstractpub_date
1996-03-15 00:00:00pages
1331-8issue
6eissn
0022-2623issn
1520-4804pii
jm950304+journal_volume
39pub_type
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