Structural Investigation of the 7-Chloro-3-hydroxy-1H-quinazoline-2,4-dione Scaffold to Obtain AMPA and Kainate Receptor Selective Antagonists. Synthesis, Pharmacological, and Molecular Modelin
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- 作者：Vittoria Colotta ; Daniela Catarzi ; Flavia Varano ; Ombretta Lenzi ; Guido Filacchioni ; Chiara Costagli ; Alessandro Galli ; Carla Ghelardini ; Nicoletta Galeotti ; Paola Gratteri ; Jacopo Sgrignani ; Francesc
- 刊名：Journal of Medicinal Chemistry
- 出版年：2006
- 出版时间：October 5, 2006
- 年：2006
- 卷：49
- 期：20
- 页码：6015 - 6026
- 全文大小：349K
- 年卷期：v.49,no.20(October 5, 2006)
- ISSN：1520-4804
文摘
In this paper, the study of new 7-chloro-3-hydroxy-1H-quinazoline-2,4-dione derivatives, designed as AMPAand kainate (KA) receptor antagonists, is reported. Some derivatives bear different carboxy-containing alkylchains on the 3-hydroxy group, while various heterocyclic rings or amide moieties are present at the 6-positionof other compounds. Binding data at Gly/NMDA, AMPA, and high-affinity KA receptors showed that thepresence of the free 3-hydroxy group is of paramount importance for a good affinity at all three investigatedreceptors, while introduction of some 6-heterocyclic moieties yielded AMPA-selective antagonists. Themost significant result was the finding of the 6-(2-carboxybenzoylamino)-3-hydroxy-1H-quinazolin-2,4-dione 12, which possesses good affinity for high-affinity and low-affinity KA receptors (Ki = 0.62 
M and1.6 M, respectively), as well as good selectivity. To rationalize the trend of affinities of the reportedderivatives, an intensive molecular modeling study was carried out by docking compounds to models of theGly/NMDA, AMPA, and KA receptors.
M and1.6 M, respectively), as well as good selectivity. To rationalize the trend of affinities of the reportedderivatives, an intensive molecular modeling study was carried out by docking compounds to models of theGly/NMDA, AMPA, and KA receptors.