Laboratory of Medicinal Chemistry, Center for Interdisciplinary Research on Medicines (CIRM), University of Liège , Quartier Hôpital B36 Av. Hippocrate 15 B-4000 Liège, Belgium.
Biostructural Research, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , DK-2100 Copenhagen, Denmark.
J Med Chem. 2018 Jan 11;61(1):251-264. doi: 10.1021/acs.jmedchem.7b01323. Epub 2017 Dec 19.
We report here the synthesis of 7-phenoxy-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides and their evaluation as AMPA receptor positive allosteric modulators (AMPApams). The impact of substitution on the phenoxy ring and on the nitrogen atom at the 4-position was examined. At GluA2(Q) expressed in HEK293 cells (calcium flux experiment), the most potent compound was 11m (4-cyclopropyl-7-(3-methoxyphenoxy)-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide, EC = 2.0 nM). The Hill coefficient in the screening and the shape of the dimerization curve in small-angle X-ray scattering (SAXS) experiments using isolated GluA2 ligand-binding domain (GluA2-LBD) are consistent with binding of one molecule of 11m per dimer interface, contrary to most benzothiadiazine dioxides developed to date. This observation was confirmed by the X-ray structure of 11m bound to GluA2-LBD and by NMR. This is the first benzothiadiazine dioxide AMPApam to reach the nanomolar range.
我们在此报告 7-苯氧基取代的 3,4-二氢-2H-1,2,4-苯并噻二嗪 1,1-二氧化物的合成及其作为 AMPA 受体正变构调节剂 (AMPApams) 的评估。考察了苯氧基环和 4 位氮原子取代对化合物的影响。在表达于 HEK293 细胞的 GluA2(Q)上（钙流实验），最有效的化合物是 11m（4-环丙基-7-(3-甲氧基苯氧基)-3,4-二氢-2H-1,2,4-苯并噻二嗪 1,1-二氧化物，EC = 2.0 nM）。在筛选中的希尔系数和使用分离的 GluA2 配体结合域 (GluA2-LBD) 的小角 X 射线散射 (SAXS) 实验中的二聚化曲线的形状与每个二聚体界面结合一个 11m 分子一致，与迄今为止开发的大多数苯并噻二嗪二氧化物相反。这一观察结果通过 11m 与 GluA2-LBD 结合的 X 射线结构和 NMR 得到了证实。这是第一个达到纳摩尔范围的苯并噻二嗪二氧 AMPApam。
