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7-Phenoxy-Substituted 3,4-Dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides as Positive Allosteric Modulators of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors with Nanomolar Potency
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-12-19 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01323
Eric Goffin 1 , Thomas Drapier 1 , Anja Probst Larsen 2 , Pierre Geubelle 1, 3 , Christopher P. Ptak 4 , Saara Laulumaa 2 , Karoline Rovinskaja 2 , Julie Gilissen 1, 3 , Pascal de Tullio 1 , Lars Olsen 2 , Karla Frydenvang 2 , Bernard Pirotte 1 , Julien Hanson 1, 3 , Robert E. Oswald 4 , Jette Sandholm Kastrup 2 , Pierre Francotte 1
Affiliation  

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, EC50 = 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.

中文翻译:

7-苯氧基取代的3,4-二氢-2 H -1,2,4-苯并噻二嗪1,1-二氧化物作为α-氨基-3-羟基-5-羟基-4-甲基-4-异恶唑丙酸(AMPA)的正变构调节剂具有纳摩尔效价的受体

我们在这里报告7-苯氧基取代的3,4-二氢-2 H -1,2,4-苯并噻二嗪1,1-二氧化物的合成及其作为AMPA受体阳性变构调节剂(AMPApams)的评估。考察了取代对苯氧基和4-位氮原子的影响。在HEK293细胞中表达的GluA2(Q)处(钙通量实验),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-2 H -1,2,4-苯并噻二嗪1,1-二氧化物,EC 50= 2.0 nM)。使用隔离的GluA2配体结合结构域(GluA2-LBD)进行的小角X射线散射(SAXS)实验中的筛选中的Hill系数和二聚化曲线的形状与每个二聚体界面结合一个11m的分子是一致的,与迄今为止开发的大多数苯并噻二嗪二氧化物相反。通过与GluA2-LBD结合的11m的X射线结构和NMR证实了该观察结果。这是第一个达到纳摩尔范围的二氧化苯并噻二嗪二甲酰胺。
更新日期:2017-12-19
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