GPCR Agonist-to-Antagonist Conversion: Enabling the Design of Nucleoside Functional Switches for the A2AAdenosine Receptor

Anna Shiriaeva, Daejin Park, Gyudong Kim, Yoonji Lee, Xiyan Hou, Dnyandev B. Jarhad, Gibae Kim, Jinha Yu, Young Eum Hyun, Woomi Kim, Zhan Guo Gao, Kenneth A. Jacobson, Gye Won Han, Raymond C. Stevens, Lak Shin Jeong, Sun Choi, Vadim Cherezov

Research output: Contribution to journalArticlepeer-review

Abstract

Modulators of the G protein-coupled A2Aadenosine receptor (A2AAR) 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 A2AAR agonist into an antagonist. We synthesized and characterized a novel A2AAR antagonist, 2 (LJ-4517), with Ki= 18.3 nM. X-ray crystallographic structures of 2 in complex with two thermostabilized A2AAR constructs were solved at 2.05 and 2.80 Å resolutions. In contrast to A2AAR agonists, which simultaneously interact with both Ser2777.42and His2787.43, 2 only transiently contacts His2787.43, which can be direct or water-mediated. The n-hexynyl group of 2 extends into an A2AAR 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.

Original languageEnglish
Pages (from-to)11648-11657
Number of pages10
JournalJournal of Medicinal Chemistry
Volume65
Issue number17
DOIs
StatePublished - 8 Sep 2022

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