5′-Substituted Amiloride Derivatives as Allosteric Modulators Binding in the Sodium Ion Pocket of the Adenosine A2A Receptor

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• 作者：Arnault Massink ; Julien Louvel ; Ilze Adlere ; Corine van Veen ; Berend J. H. Huisman ; Gabrielle S. Dijksteel ; Dong Guo ; Eelke B. Lenselink ; Benjamin J. Buckley ; Hayden Matthews ; Marie Ranson ; Michael Kelso ; Adriaan P. IJzerman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：May 26, 2016
• 年：2016
• 卷：59
• 期：10
• 页码：4769-4777
• 全文大小：475K
• 年卷期：0
• ISSN：1520-4804

文摘

The sodium ion site is an allosteric site conserved among many G protein-coupled receptors (GPCRs). Amiloride 1 and 5-(N,N-hexamethylene)amiloride 2 (HMA) supposedly bind in this sodium ion site and can influence orthosteric ligand binding. The availability of a high-resolution X-ray crystal structure of the human adenosine A_2A receptor (hA_2AAR), in which the allosteric sodium ion site was elucidated, makes it an appropriate model receptor for investigating the allosteric site. In this study, we report the synthesis and evaluation of novel 5′-substituted amiloride derivatives as hA_2AAR allosteric antagonists. The potency of the amiloride derivatives was assessed by their ability to displace orthosteric radioligand [³H]4-(2-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a]-[1,3,5]triazin-5-yl)amino)ethyl)phenol ([³H]ZM-241,385) from both the wild-type and sodium ion site W246A mutant hA_2AAR. 4-Ethoxyphenethyl-substituted amiloride 12l was found to be more potent than both amiloride and HMA, and the shift in potency between the wild-type and mutated receptor confirmed its likely binding to the sodium ion site.