Catarzi Daniela, Colotta Vittoria, Varano Flavia, Calabri Francesca Romana, Filacchioni Guido, Galli Alessandro, Costagli Chiara, Carlà Vincenzo
Dipartimento di Scienze Farmaceutiche, Polo Scientifico, Universita'degli Studi di Firenze, Via Ugo Schiff, 6, Sesto Fiorentino (FI), Italy.
J Med Chem. 2004 Jan 1;47(1):262-72. doi: 10.1021/jm030906q.
In recent papers (Catarzi, D.; et al. J. Med. Chem. 2000, 43, 3824-3826; 2001, 44, 3157-3165) we reported chemical and biological studies on 4,5-dihydro-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylates (TQXs) bearing different nitrogen-containing heterocycles at position-8. In particular, from these studies it emerged that both the 7-chloro-4,5-dihydro-4-oxo-8-(1,2,4-triazol-4-yl)-1,2,4-triazolo[1,5-a] quinoxaline-2-carboxylic acid TQX-173 (compound B) and its corresponding ethyl ester (compound A) were the most active and selective compounds of this series. In pursuing our investigation on the structure-activity relationships of these TQX derivatives, different electron-withdrawing groups (CF(3), NO(2)) were introduced at position 7 on the TQX ring system, replacing the 7-chloro substituent of B and of other selected 8-heteroaryltriazoloquinoxaline-2-carboxylates previously described. All the newly synthesized compounds were biologically evaluated for their binding at the Gly/NMDA, AMPA, and KA high-affinity receptors. Gly/NMDA binding assays were performed to assess the selectivity of the reported compounds toward the AMPA receptor. Compounds endowed with micromolar binding affinity for the KA high-affinity binding site were also evaluated for their binding at the KA low-affinity receptor. Some selected compounds were also tested for their functional antagonist activity at the AMPA and NMDA receptor-ion channel complex. The results obtained in this study have pointed out that 4,5-dihydro-7-nitro-4-oxo-8-(3-carboxypyrrol-1-yl)-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylic acid (9b) and its corresponding ethyl ester (9a) are the most potent and selective AMPA receptor antagonists reported to date among the TQX series.
在最近的论文中（卡塔齐，D.；等人，《药物化学杂志》，2000年，43卷，3824 - 3826页；2001年，44卷，3157 - 3165页），我们报道了对4,5 - 二氢 - 4 - 氧代 - 1,2,4 - 三唑并[1,5 - a]喹喔啉 - 2 - 羧酸酯（TQXs）的化学和生物学研究，这些化合物在8位带有不同的含氮杂环。特别地，从这些研究中发现，7 - 氯 - 4,5 - 二氢 - 4 - 氧代 - 8 -（1,2,4 - 三唑 - 4 - 基）- 1,2,4 - 三唑并[1,5 - a]喹喔啉 - 2 - 羧酸TQX - 173（化合物B）及其相应的乙酯（化合物A）是该系列中活性和选择性最高的化合物。在继续我们对这些TQX衍生物构效关系的研究中，在TQX环系统的7位引入了不同的吸电子基团（CF(3)、NO(2)），取代了B以及先前描述的其他选定的8 - 杂芳基三唑并喹喔啉 - 2 - 羧酸酯的7 - 氯取代基。对所有新合成的化合物进行了生物学评估，以检测它们与甘氨酸/NMDA、AMPA和KA高亲和力受体的结合情况。进行甘氨酸/NMDA结合试验以评估所报道化合物对AMPA受体的选择性。对那些对KA高亲和力结合位点具有微摩尔结合亲和力的化合物，也评估了它们与KA低亲和力受体的结合情况。还测试了一些选定化合物在AMPA和NMDA受体 - 离子通道复合物上的功能拮抗活性。本研究获得的结果指出，4,5 - 二氢 - 7 - 硝基 - 4 - 氧代 - 8 -（3 - 羧基吡咯 - 1 - 基）- 1,2,4 - 三唑并[1,5 - a]喹喔啉 - 2 - 羧酸（9b）及其相应的乙酯（9a）是TQX系列中迄今为止报道的最有效和最具选择性的AMPA受体拮抗剂。
