| Autor: |
Jörg M; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria 3052, Australia., Glukhova A; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences Biology, and Department of Pharmacology, Monash University , Parkville, Victoria 3052, Australia., Abdul-Ridha A; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences Biology, and Department of Pharmacology, Monash University , Parkville, Victoria 3052, Australia., Vecchio EA; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences Biology, and Department of Pharmacology, Monash University , Parkville, Victoria 3052, Australia., Nguyen AT; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences Biology, and Department of Pharmacology, Monash University , Parkville, Victoria 3052, Australia., Sexton PM; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences Biology, and Department of Pharmacology, Monash University , Parkville, Victoria 3052, Australia., White PJ; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences Biology, and Department of Pharmacology, Monash University , Parkville, Victoria 3052, Australia., May LT; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences Biology, and Department of Pharmacology, Monash University , Parkville, Victoria 3052, Australia., Christopoulos A; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences Biology, and Department of Pharmacology, Monash University , Parkville, Victoria 3052, Australia., Scammells PJ; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria 3052, Australia. |
| Abstrakt: |
The A 1 adenosine receptor (A 1 AR) is an important G protein-coupled receptor that regulates a range of physiological functions. Herein we report the discovery of novel irreversible agonists acting at the A 1 AR, which have the potential to serve as useful research tools for studying receptor structure and function. A series of novel adenosine derivatives bearing electrophilic substituents was synthesized, and four compounds, 8b, 15a, 15b, and 15d, were shown to possess similar potency and efficacy to the reference high efficacy agonist, NECA, in an assay of ERK1/2 phosphorylation assay. Insensitivity to antagonist addition in a real-time, label-free, xCELLigence assay was subsequently used to identify compounds that likely mediated their agonism through an irreversible interaction with the A 1 AR. Of these compounds, 15b and 15d were more directly validated as irreversible agonists of the A 1 AR using membrane-based [ 3 H]DPCPX and [ 35 S]GTPγS binding experiments. |
