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

被引：5

作者：

Beerkens, Bert L. H. ^{[1
]}

Wang, Xuesong ^{[1
]}

Avgeropoulou, Maria ^{[1
]}

Adistia, Lisa N. ^{[1
]}

van Veldhoven, Jacobus P. D. ^{[1
]}

Jespers, Willem ^{[1
]}

Liu, Rongfang ^{[1
]}

Heitman, Laura H. ^{[1
]}

IJzerman, Adriaan P. ^{[1
]}

van der Es, Daan ^{[1
]}

机构：

[1] Leiden Univ, Leiden Acad Ctr Drug Res, Div Drug Discovery & Safety, Einsteinweg 55, NL-2333 CC Leiden, Netherlands

来源：

RSC MEDICINAL CHEMISTRY | 2022年 / 13卷 / 07期

关键词：

INTERNATIONAL UNION; ANTAGONISTS; XANTHINES; DERIVATIVES; A(1); POTENT; CLASSIFICATION; NOMENCLATURE; PHARMACOLOGY; WARHEADS;

D O I：

10.1039/d2md00132b

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：850 / 856

页数：7

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