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Development of Covalent, Clickable Probes for Adenosine A1 and A3 Receptors.
Trinh, Phuc N H; Chong, Daniel J W; Leach, Katie; Hill, Stephen J; Tyndall, Joel D A; May, Lauren T; Vernall, Andrea J; Gregory, Karen J.
Afiliación
  • Trinh PNH; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, and Department of Pharmacology, Monash University, Parkville, VIC 3052, Australia.
  • Chong DJW; School of Pharmacy, University of Otago, Dunedin 9016, New Zealand.
  • Leach K; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, and Department of Pharmacology, Monash University, Parkville, VIC 3052, Australia.
  • Hill SJ; Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, The Midlands NG7 2UH, U.K.
  • Tyndall JDA; Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, U.K.
  • May LT; School of Pharmacy, University of Otago, Dunedin 9016, New Zealand.
  • Vernall AJ; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, and Department of Pharmacology, Monash University, Parkville, VIC 3052, Australia.
  • Gregory KJ; Department of Chemistry, University of Otago, Dunedin 9016, New Zealand.
J Med Chem ; 64(12): 8161-8178, 2021 06 24.
Article en En | MEDLINE | ID: mdl-34120444
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Xantinas / Sondas Moleculares / Receptor de Adenosina A1 / Receptor de Adenosina A3 / Antagonistas del Receptor de Adenosina A1 / Antagonistas del Receptor de Adenosina A3 Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2021 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Xantinas / Sondas Moleculares / Receptor de Adenosina A1 / Receptor de Adenosina A3 / Antagonistas del Receptor de Adenosina A1 / Antagonistas del Receptor de Adenosina A3 Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2021 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos