The past fifty years have been marked by the surge of neurodegenerative diseases. Unfortunately, current treatments are only symptomatic. Hence, the search for new and innovative therapeutic targets for curative treatments becomes a major challenge. Among these targets, the adenosine A_2A receptor (A_2AAR) has been the subject of much research in recent years. In this paper, we report the design, synthesis and pharmacological analysis of quinazoline derivatives as A_2AAR antagonists with high ligand efficiency. This class of molecules has been discovered by a virtual screening and bears no structural semblance with reference antagonist ZM-241385. More precisely, we identified a series of 2-aminoquinazoline as promising A_2AAR antagonists. Among them, one compound showed a high affinity towards A_2AAR (21a, K_i = 20 nM). We crystallized this ligand in complex with A_2AAR, confirming one of our predicted docking poses and opening up possibilities for further optimization to derive selective ligands for specific adenosine receptor subtypes.

过去五十年的特点是神经退行性疾病激增。不幸的是，目前的治疗只是对症。因此，为治愈性治疗寻找新的和创新的治疗靶点成为一项重大挑战。在这些靶标中，腺苷A _2A受体(A _2A AR) 已成为近年来大量研究的主题。在本文中，我们报告了喹唑啉衍生物作为具有高配体效率的 A _{2A AR 拮抗剂的设计、合成和药理学分析。}这类分子是通过虚拟筛选发现的，与参考拮抗剂 ZM-241385 没有结构相似性。更准确地说，我们确定了一系列 2-氨基喹唑啉作为有前途的 A _2AAR拮抗剂。其中，一种化合物对A _2A AR ( 21a , K _i  = 20 nM)表现出高亲和力。我们将这种配体与 A _2A AR 复合结晶，证实了我们预测的对接姿势之一，并为进一步优化以获得特定腺苷受体亚型的选择性配体开辟了可能性。