Laboratory of Medicinal Chemistry, Center for Interdisciplinary Research on Medicines (CIRM) , ULiège , Quartier Hôpital, Avenue Hippocrate, 15, B36 , B-4000 Liège , Belgium.
Laboratory of Molecular Pharmacology, GIGA-Molecular Biology of Diseases , ULiège , B34, Quartier Hôpital, Avenue de l'hôpital, 11 , B-4000 Liège , Belgium.
J Med Chem. 2018 Jun 28;61(12):5279-5291. doi: 10.1021/acs.jmedchem.8b00250. Epub 2018 Jun 8.
The present study describes the identification of highly potent dimeric 1,2,4-benzothiadiazine 1,1-dioxide (BTD)-type positive allosteric modulators of the AMPA receptors (AMPApams) obtained by linking two monomeric BTD scaffolds through their respective 6-positions. Using previous X-ray data from monomeric BTDs cocrystallized with the GluA2 ligand-binding domain (LBD), a molecular modeling approach was performed to predict the preferred dimeric combinations. Two 6,6-ethylene-linked dimeric BTD compounds (16 and 22) were prepared and evaluated as AMPApams on HEK293 cells expressing GluA2( Q) (calcium flux experiment). These compounds were found to be about 10,000 times more potent than their respective monomers, the most active dimeric compound being the bis-4-cyclopropyl-substituted compound 22 [6,6'-(ethane-1,2-diyl)bis(4-cyclopropyl-3,4-dihydro-2 H-1,2,4-benzothiadiazine 1,1-dioxide], with an EC value of 1.4 nM. As a proof of concept, the bis-4-methyl-substituted dimeric compound 16 (EC = 13 nM) was successfully cocrystallized with the GluA2-LBD and was found to occupy the two BTD binding sites at the LBD dimer interface.
本研究描述了通过将两个单体苯并噻二嗪 1,1-二氧化物（BTD）支架在各自的 6 位连接来鉴定高活性二聚体 1,2,4-苯并噻二嗪 1,1-二氧化物（BTD）型 AMPA 受体（AMPApams）的正变构调节剂。使用先前与 GluA2 配体结合域（LBD）共结晶的单体 BTD 的 X 射线数据，采用分子建模方法预测了首选的二聚体组合。制备了两个 6,6-亚乙基连接的二聚体 BTD 化合物（16 和 22），并作为在表达 GluA2(Q)（钙通量实验）的 HEK293 细胞上的 AMPApams 进行了评估。这些化合物的活性比其各自的单体高约 10,000 倍，最活性的二聚体化合物是双 4-环丙基取代的化合物 22[6,6'-(乙烷-1,2-二基)双(4-环丙基-3,4-二氢-2 H-1,2,4-苯并噻二嗪 1,1-二氧化物]，EC 值为 1.4 nM。作为概念验证，双 4-甲基取代的二聚体化合物 16（EC = 13 nM）成功地与 GluA2-LBD 共结晶，并发现其占据 LBD 二聚体界面上的两个 BTD 结合位点。
