Development of subtype-selective covalent ligands for the adenosine A2B receptor by tuning the reactive group
| Autor: | Beerkens, B.L.H., Wang, X., Avgeropoulou, M., Adistia, L.N., Veldhoven, J.P.D. van, Jespers, W., Liu, R., Heitman, L.H., IJzerman, A.P., Es, D. van der |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | RSC Med Chem RSC Medicinal Chemistry, 13(7), 850-856. Royal Society of Chemistry ({RSC}) |
| Popis: | Signalling through the adenosine receptors (ARs), in particular through the adenosine A(2B) receptor (A(2B)AR), has been shown to play a role in a variety of pathological conditions, ranging from immune disorders to cancer. Covalent ligands for the A(2B)AR have the potential to irreversibly block the receptor, as well as inhibit all A(2B)AR-induced signalling pathways. This will allow a thorough investigation of the pathophysiological role of the receptor. In this study, we synthesized and evaluated a set of potential covalent ligands for the A(2B)AR. The ligands all contain a core scaffold consisting of a substituted xanthine, varying in type and orientation of electrophilic group (warhead). Here, we find that the right combination of these variables is necessary for a high affinity, irreversible mode of binding and selectivity towards the A(2B)AR. Altogether, this is the case for sulfonyl fluoride 24 (LUF7982), a covalent ligand that allows for novel ways to interrogate the A(2B)AR. |
| Databáze: | OpenAIRE |
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