2. Academic Validation
  3. GPCR Agonist-to-Antagonist Conversion: Enabling the Design of Nucleoside Functional Switches for the A2A Adenosine Receptor

GPCR Agonist-to-Antagonist Conversion: Enabling the Design of Nucleoside Functional Switches for the A2A Adenosine Receptor

  • J Med Chem. 2022 Sep 8;65(17):11648-11657. doi: 10.1021/acs.jmedchem.2c00462.
Anna Shiriaeva 1 2,  Daejin Park 3,  Gyudong Kim 4 5,  Yoonji Lee 6,  Xiyan Hou 4,  Dnyandev B Jarhad 4,  Gibae Kim 4,  Jinha Yu 4,  Young Eum Hyun 4,  Woomi Kim 3,  Zhan-Guo Gao 7,  Kenneth A Jacobson 7,  Gye Won Han 1 2,  Raymond C Stevens 1 2 8,  Lak Shin Jeong 4,  Sun Choi 9,  Vadim Cherezov 1 2
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Southern California, Los Angeles, California 90089, United States.
  • 2 Bridge Institute, University of Southern California, Los Angeles, California 90089, United States.
  • 3 Department of Pharmacology, Kosin University College of Medicine, Busan 49267, Republic of Korea.
  • 4 Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
  • 5 College of Pharmacy & Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea.
  • 6 College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea.
  • 7 Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892, United States.
  • 8 Structure Therapeutics, 701 Gateway Blvd, South San Francisco, California 94080, United States.
  • 9 Global AI Drug Discovery Center, College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
PMID: 35977382 DOI: 10.1021/acs.jmedchem.2c00462
Abstract

Modulators of the G protein-coupled A2A Adenosine 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 Ser2777.42 and 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.

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