Synthesis, Pharmacological and Structural Characterization, and Thermodynamic Aspects of GluA2-Positive Allosteric Modulators with a 3,4-Dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxide Scaffold

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• 作者：Ann-Beth N酶rholm ; Pierre Francotte ; Lars Olsen ; Christian Krintel ; Karla Frydenvang ; Eric Goffin ; Sylvie Challal ; Laurence Danober ; Iuliana Botez-Pop ; Pierre Lestage ; Bernard Pirotte ; Jette S. Kastrup
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 14, 2013
• 年：2013
• 卷：56
• 期：21
• 页码：8736-8745
• 全文大小：470K
• 年卷期：v.56,no.21(November 14, 2013)
• ISSN：1520-4804

文摘

Positive allosteric modulators of ionotropic glutamate receptors are potential compounds for treatment of cognitive disorders, e.g., Alzheimer鈥檚 disease. The modulators bind within the dimer interface of the ligand-binding domain (LBD) and stabilize the agonist-bound conformation, thereby slowing receptor desensitization and/or deactivation. Here we describe the synthesis and pharmacological testing at GluA2 of a new generation of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides. The most potent modulator 3 in complex with GluA2-LBD-L483Y-N754S was subjected to structural analysis by X-ray crystallography, and the thermodynamics of binding was studied by isothermal titration calorimetry. Compound 3 binds to GluA2-LBD-L483Y-N754S with a K_d of 0.35 渭M (螖H = 鈭?.5 kcal/mol and 鈭?i>T螖S = 鈭?.3 kcal/mol). This is the first time that submicromolar binding affinity has been achieved for this type of positive allosteric modulator. The major structural factor increasing the binding affinity of 3 seems to be interactions between the cyclopropyl group of 3 and the backbone of Phe495 and Met496.