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

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. This journal is © The Royal Society of Chemistry.