Department of Chemistry, University of Southern California, Los Angeles, California 90089, United States.
Bridge Institute, University of Southern California, Los Angeles, California 90089, United States.
J Med Chem. 2022 Sep 8;65(17):11648-11657. doi: 10.1021/acs.jmedchem.2c00462. Epub 2022 Aug 17.
Modulators of the G protein-coupled A adenosine receptor (AAR) have been considered promising agents to treat Parkinson's disease, inflammation, cancer, and central nervous system disorders. Herein, we demonstrate that a thiophene modification at the C8 position in the common adenine scaffold converted an AAR agonist into an antagonist. We synthesized and characterized a novel AAR antagonist, (LJ-4517), with = 18.3 nM. X-ray crystallographic structures of in complex with two thermostabilized AAR constructs were solved at 2.05 and 2.80 Å resolutions. In contrast to AAR agonists, which simultaneously interact with both Ser277 and His278, only transiently contacts His278, which can be direct or water-mediated. The -hexynyl group of extends into an AAR exosite. Structural analysis revealed that the introduced thiophene modification restricted receptor conformational rearrangements required for subsequent activation. This approach can expand the repertoire of adenosine receptor antagonists that can be designed based on available agonist scaffolds.
G 蛋白偶联 A 腺苷受体（AAR）调节剂被认为是治疗帕金森病、炎症、癌症和中枢神经系统疾病的有希望的药物。本文中，我们证明在常见腺嘌呤支架的 C8 位引入噻吩基可将 AAR 激动剂转换为拮抗剂。我们合成并表征了一种新型 AAR 拮抗剂 LJ-4517，其 = 18.3 nM。通过 2.05 和 2.80 Å 的分辨率解析了与两种热稳定 AAR 构建体形成复合物的 LJ-4517 的 X 射线晶体结构。与同时与 Ser277 和 His278 相互作用的 AAR 激动剂不同，LJ-4517 仅瞬时接触 His278，这种接触可以是直接的或通过水介导的。LJ-4517 的 -己炔基延伸到 AAR 外位点。结构分析表明，引入的噻吩基修饰限制了受体构象重排，这是随后激活所必需的。这种方法可以扩展基于现有激动剂支架设计的腺苷受体拮抗剂的种类。
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