Division of Organic Chemistry, Lund University, PO Box 124, SE-221 00 Lund, Sweden.
Bioorg Med Chem. 2011 Jan 1;19(1):111-21. doi: 10.1016/j.bmc.2010.11.050. Epub 2010 Nov 25.
Based on a pharmacophore model of the benzodiazepine-binding site of GABA(A) receptors, a series of 2-aryl-2,6-dihydro[1,2,4]triazolo[4,3-c]quinazoline-3,5-diones (structure type I) were designed, synthesized, and identified as high-affinity ligands of the binding site. For several compounds, K(i) values of around 0.20nM were determined. They show a structural resemblance with the previously described 2-phenyl-2H-pyrazolo[4,3-c]quinolin-3(5H)-ones (II) and 2-phenyl-[1,2,4]triazolo[1,5-a]quinoxalin-4(5H)-one (III). The 9-bromo substituted compounds 8a-d were prepared in an 8-step synthesis in an overall yield of approximately 40%, and a library of 9-substituted analogues was prepared by cross-coupling reactions. Compound 8e, 21, 22, and 24 were tested on recombinant rat α(1)β(3)γ(2), α(2)β(3)γ(2), α(3)β(3)γ(2), and α(5)β(3)γ(2) subtypes, and displayed selectivity for the α(1)β(3)γ(2) isoform.
基于 GABA(A) 受体苯二氮䓬结合位点的药效基团模型，设计、合成并鉴定了一系列 2-芳基-2,6-二氢[1,2,4]三唑并[4,3-c]喹唑啉-3,5-二酮（结构类型 I），它们是该结合位点的高亲和力配体。对于几种化合物，确定了约 0.20nM 的 K(i) 值。它们与先前描述的 2-苯基-2H-吡唑并[4,3-c]喹啉-3(5H)-酮（II）和 2-苯基-[1,2,4]三唑并[1,5-a]喹喔啉-4(5H)-酮（III）具有结构相似性。9-溴取代的化合物 8a-d 通过 8 步合成以约 40%的总收率制备，并且通过交叉偶联反应制备了 9-取代的类似物文库。化合物 8e、21、22 和 24 在重组大鼠 α(1)β(3)γ(2)、α(2)β(3)γ(2)、α(3)β(3)γ(2)和 α(5)β(3)γ(2)亚型上进行了测试，对 α(1)β(3)γ(2)同工型显示出选择性。
