Discovery of a new human A2A adenosine receptor agonist, truncated 2-hexynyl-4′-thioadenosine

Xiyan Hou, Hea Ok Kim, Varughese Alexander, Kyunglim Kim, Sun Choi, Seul Gi Park, Jin Hee Lee, Lena S. Yoo, Zhan Guo Gao, Kenneth A. Jacobson, Lak Shin Jeong

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


The truncated C2- and C8-substituted 4′-thioadenosine derivatives 4a-d were synthesized from d-mannose, using palladium-catalyzed cross-coupling reactions as key steps. In this study, an A3 adenosine receptor (AR) antagonist, truncated 4′-thioadenosine derivative 3, was successfully converted into a potent A2A AR agonist 4a (Ki = 7.19 ± 0.6 nM) by appending a 2-hexynyl group at the C2-position of a derivative of 3 that was N6-substituted. However, C8-substitution greatly reduced binding affinity at the human A2A AR. All synthesized compounds 4a-d maintained their affinity at the human A3 AR, but 4a was found to be a competitive A3 AR antagonist/A2A AR agonist in cyclic AMP assays. This study indicates that the truncated C2-substituted 4′-thioadenosine derivatives 4a and 4b can serve as novel templates for the development of new A2A AR ligands.

Original languageEnglish
Pages (from-to)516-520
Number of pages5
JournalACS Medicinal Chemistry Letters
Issue number9
StatePublished - 9 Dec 2010


  • A adenosine receptor agonists
  • binding mode
  • palladium-catalyzed cross-coupling reactions
  • truncated 2-hexynyl-4′- thioadenosine


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