Development of Covalent, Clickable Probes for Adenosine A1 and A3 Receptors
| Autor: | Lauren T. May, Stephen J. Hill, Joel D. A. Tyndall, Daniel J W Chong, Katie Leach, Karen J. Gregory, Phuc N. H. Trinh, Andrea J. Vernall |
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| Rok vydání: | 2021 |
| Předmět: |
0303 health sciences
Drug discovery Xanthine Adenosine A3 receptor 01 natural sciences Adenosine receptor 0104 chemical sciences 010404 medicinal & biomolecular chemistry 03 medical and health sciences chemistry.chemical_compound Adenosine A1 receptor chemistry Biochemistry Drug Discovery Click chemistry Molecular Medicine Receptor Bifunctional 030304 developmental biology |
| Zdroj: | Journal of Medicinal Chemistry. 64:8161-8178 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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