Structure–Activity Relationship of Adenosine 5′-diphosphoribose at the Transient Receptor Potential Melastatin 2 (TRPM2) Channel: Rational Design of Antagonists

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• 作者：Christelle Moreau ; Tanja Kirchberger ; Joanna M. Swarbrick ; Stephen J. Bartlett ; Ralf Fliegert ; Timur Yorgan ; Andreas Bauche ; Angelika Harneit ; Andreas H. Guse ; Barry V. L. Potter
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：December 27, 2013
• 年：2013
• 卷：56
• 期：24
• 页码：10079-10102
• 全文大小：1217K
• ISSN：1520-4804

文摘

Adenosine 5鈥?diphosphoribose (ADPR) activates TRPM2, a Ca²⁺, Na⁺, and K⁺ permeable cation channel. Activation is induced by ADPR binding to the cytosolic C-terminal NudT9-homology domain. To generate the first structure鈥揳ctivity relationship, systematically modified ADPR analogues were designed, synthesized, and evaluated as antagonists using patch-clamp experiments in HEK293 cells overexpressing human TRPM2. Compounds with a purine C8 substituent show antagonist activity, and an 8-phenyl substitution (8-Ph-ADPR, 5) is very effective. Modification of the terminal ribose results in a weak antagonist, whereas its removal abolishes activity. An antagonist based upon a hybrid structure, 8-phenyl-2鈥?deoxy-ADPR (86, IC₅₀ = 3 渭M), is more potent than 8-Ph-ADPR (5). Initial bioisosteric replacement of the pyrophosphate linkage abolishes activity, but replacement of the pyrophosphate and the terminal ribose by a sulfamate-based group leads to a weak antagonist, a lead to more drug-like analogues. 8-Ph-ADPR (5) inhibits Ca²⁺ signalling and chemotaxis in human neutrophils, illustrating the potential for pharmacological intervention at TRPM2.