通过调节反应基团开发腺苷 A 受体的亚型选择性共价配体。
Development of subtype-selective covalent ligands for the adenosine A receptor by tuning the reactive group.
作者信息
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
机构信息
Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University Einsteinweg 55 2333 CC Leiden The Netherlands
出版信息
RSC Med Chem. 2022 Jun 21;13(7):850-856. doi: 10.1039/d2md00132b. eCollection 2022 Jul 20.
Signalling through the adenosine receptors (ARs), in particular through the adenosine A receptor (AAR), has been shown to play a role in a variety of pathological conditions, ranging from immune disorders to cancer. Covalent ligands for the AAR have the potential to irreversibly block the receptor, as well as inhibit all AAR-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 AAR. 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 AAR. Altogether, this is the case for sulfonyl fluoride 24 (LUF7982), a covalent ligand that allows for novel ways to interrogate the AAR.
通过腺苷受体（ARs）发出信号，特别是通过腺苷A受体（AAR）发出信号，已被证明在从免疫紊乱到癌症等多种病理状况中发挥作用。AAR的共价配体有可能不可逆地阻断该受体，并抑制所有AAR诱导的信号通路。这将允许对该受体的病理生理作用进行全面研究。在本研究中，我们合成并评估了一组潜在的AAR共价配体。这些配体均含有一个由取代黄嘌呤组成的核心骨架，亲电基团（弹头）的类型和方向各不相同。在此，我们发现这些变量的正确组合对于高亲和力、不可逆的结合模式以及对AAR的选择性是必要的。总体而言，磺酰氟24（LUF7982）就是这种情况，它是一种共价配体，为研究AAR提供了新方法。
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