Loratadine and Analogues: Discovery and Preliminary Structure鈥揂ctivity Relationship of Inhibitors of the Amino Acid Transporter B0AT2

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• 作者：Serena Cuboni ; Christian Devigny ; Bastiaan Hoogeland ; Andrea Strasser ; Sebastian Pomplun ; Barbara Hauger ; Georg H枚fner ; Klaus T. Wanner ; Matthias Eder ; Armin Buschauer ; Florian Holsboer ; Felix Hausch
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：November 26, 2014
• 年：2014
• 卷：57
• 期：22
• 页码：9473-9479
• 全文大小：324K
• ISSN：1520-4804

文摘

B⁰AT2, encoded by the SLC6A15 gene, is a transporter for neutral amino acids that has recently been implicated in mood and metabolic disorders. It is predominantly expressed in the brain, but little is otherwise known about its function. To identify inhibitors for this transporter, we screened a library of 3133 different bioactive compounds. Loratadine, a clinically used histamine H₁ receptor antagonist, was identified as a selective inhibitor of B⁰AT2 with an IC₅₀ of 4 渭M while being less active or inactive against several other members of the SLC6 family. Reversible inhibition of B⁰AT2 was confirmed by electrophysiology. A series of loratadine analogues were synthesized to gain insight into the structure鈥揳ctivity relationships. Our studies provide the first chemical tool for B⁰AT2.