5′-Substituted Amiloride Derivatives as Allosteric Modulators Binding in the Sodium Ion Pocket of the Adenosine A2A Receptor
| Autor: | Berend J. H. Huisman, Marie Ranson, Dong Guo, Ilze Adlere, Corine van Veen, Arnault Massink, Eelke B. Lenselink, Gabrielle S. Dijksteel, Michael J. Kelso, Hayden Matthews, Benjamin J. Buckley, Adriaan P. IJzerman, Julien Louvel |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Receptor Adenosine A2A Stereochemistry Sodium Mutant Allosteric regulation chemistry.chemical_element Adenosine A2A receptor Amiloride Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Allosteric Regulation Drug Discovery Radioligand medicine Humans Receptor G protein-coupled receptor Molecular Structure Chemistry Adenosine A2 Receptor Antagonists 3. Good health Molecular Docking Simulation 030104 developmental biology Biochemistry 030220 oncology & carcinogenesis Molecular Medicine Allosteric Site medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 59:4769-4777 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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 A2A receptor (hA2AAR), 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 hA2AAR allosteric antagonists. The potency of the amiloride derivatives was assessed by their ability to displace orthosteric radioligand [(3)H]4-(2-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a]-[1,3,5]triazin-5-yl)amino)ethyl)phenol ([(3)H]ZM-241,385) from both the wild-type and sodium ion site W246A mutant hA2AAR. 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. |
| Databáze: | OpenAIRE |
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