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Modification and Functionalization of the Guanidine Group by Tailor-made Precursors
Published on: April 27, 2017
Development of subtype-selective covalent ligands for the adenosine A2B receptor by tuning the reactive group
Bert L H Beerkens1, Xuesong Wang1, Maria Avgeropoulou1
1Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University Einsteinweg 55 2333 CC Leiden The Netherlands d.van.der.es@lacdr.leidenuniv.nl.
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.
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