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

• Published in: MedChemComm Vol. 13; no. 7; pp. 850 - 856
• Main Authors: Beerkens, Bert L. H., Wang, Xuesong, Avgeropoulou, Maria, Adistia, Lisa N., van Veldhoven, Jacobus P. D., Jespers, Willem, Liu, Rongfang, Heitman, Laura H., IJzerman, Adriaan P., van der Es, Daan
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 20.07.2022; Royal Society of Chemistry; RSC
• Subjects: Adenosine; Adenosine receptors; Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Covalence; Fluorides; Life Sciences & Biomedicine; Ligands; Pharmacology & Pharmacy; Receptors; Science & Technology; Selectivity; Signal transduction; Signaling; A; POTENT; NOMENCLATURE; INTERNATIONAL UNION; XANTHINES; WARHEADS; PHARMACOLOGY; CLASSIFICATION; ANTAGONISTS; DERIVATIVES
• ISSN: 2040-2503; 2632-8682; 2632-8682; 2040-2511
• DOI: 10.1039/d2md00132b

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.