Development of subtype-selective covalent ligands for the adenosine A 2B receptor by tuning the reactive group.

Autor: Beerkens BLH; Division 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., Wang X; Division 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., Avgeropoulou M; Division 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., Adistia LN; Division 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., van Veldhoven JPD; Division 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., Jespers W; Division 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., Liu R; Division 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., Heitman LH; Division 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., IJzerman AP; Division 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., van der Es D; Division 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.
Jazyk: angličtina
Zdroj: RSC medicinal chemistry [RSC Med Chem] 2022 Jun 21; Vol. 13 (7), pp. 850-856. Date of Electronic Publication: 2022 Jun 21 (Print Publication: 2022).
DOI: 10.1039/d2md00132b
Abstrakt: 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.
Competing Interests: The authors declare no conflicts of interest.
(This journal is © The Royal Society of Chemistry.)
Databáze: MEDLINE
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