Issue 7, 2022

Development of subtype-selective covalent ligands for the adenosine A2B receptor by tuning the reactive group

Abstract

Signalling through the adenosine receptors (ARs), in particular through the adenosine A2B receptor (A2BAR), has been shown to play a role in a variety of pathological conditions, ranging from immune disorders to cancer. Covalent ligands for the A2BAR have the potential to irreversibly block the receptor, as well as inhibit all A2BAR-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 A2BAR. 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 A2BAR. Altogether, this is the case for sulfonyl fluoride 24 (LUF7982), a covalent ligand that allows for novel ways to interrogate the A2BAR.

Graphical abstract: Development of subtype-selective covalent ligands for the adenosine A2B receptor by tuning the reactive group

Supplementary files

Article information

Article type
Research Article
Submitted
29 رمضان 1443
Accepted
19 ذو القعدة 1443
First published
22 ذو القعدة 1443

RSC Med. Chem., 2022,13, 850-856

Development of subtype-selective covalent ligands for the adenosine A2B receptor by tuning the reactive group

B. L. H. Beerkens, X. Wang, M. Avgeropoulou, L. N. Adistia, J. P. D. van Veldhoven, W. Jespers, R. Liu, L. H. Heitman, A. P. IJzerman and D. van der Es, RSC Med. Chem., 2022, 13, 850 DOI: 10.1039/D2MD00132B

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements