Development of Covalent, Clickable Probes for Adenosine A1and A3Receptors

Phuc N.H. Trinh, Daniel J.W. Chong, Katie Leach, Stephen J. Hill, Joel D.A. Tyndall, Lauren T. May, Andrea J. Vernall, Karen J. Gregory

Research output: Contribution to journalArticleResearchpeer-review

7 Citations (Scopus)


Adenosine receptors are attractive therapeutic targets for multiple conditions, including ischemia-reperfusion injury and neuropathic pain. Adenosine receptor drug discovery efforts would be facilitated by the development of appropriate tools to assist in target validation and direct receptor visualization in different native environments. We report the development of the first bifunctional (chemoreactive and clickable) ligands for the adenosine A1 receptor (A1R) and adenosine A3 receptor (A3R) based on an orthosteric antagonist xanthine-based scaffold and on an existing structure-activity relationship. Bifunctional ligands were functional antagonists with nanomolar affinity and irreversible binding at the A1R and A3R. In-depth pharmacological profiling of these bifunctional ligands showed moderate selectivity over A2A and A2B adenosine receptors. Once bound to the receptor, ligands were successfully "clicked"with a cyanine-5 fluorophore containing the complementary "click"partner, enabling receptor detection. These bifunctional ligands are expected to aid in the understanding of A1R and A3R localization and trafficking in native cells and living systems.

Original languageEnglish
Pages (from-to)8161–8178
Number of pages18
JournalJournal of Medicinal Chemistry
Issue number12
Publication statusPublished - 14 Jun 2021

Cite this