321907-05-5Relevant articles and documents
Fluorosulfonyl-substituted xanthines as selective irreversible antagonists for the A1-adenosine receptor
Beauglehole,Baker,Scammells
, p. 4973 - 4980 (2000)
FSCPX (1) has been reported to be a potent, selective, and irreversible antagonist for the A1-adenosine receptor (AR). To obtain an irreversible A1AR antagonist with potentially better stability and to further elucidate the effects o
Design and pharmacological profile of a novel covalent partial agonist for the adenosine A1 receptor
Burggraaff, Lindsey,Dilweg, Majlen A.,Heitman, Laura H.,IJzerman, Adriaan P.,Osemwengie, Dion,Yang, Xue,van der Es, Daan
, (2020)
Partial agonists for G protein-coupled receptors (GPCRs) provide opportunities for novel pharmacotherapies with enhanced on-target safety compared to full agonists. For the human adenosine A1 receptor (hA1AR) this has led to the discovery of capadenoson, which has been in phase IIa clinical trials for heart failure. Accordingly, the design and profiling of novel hA1AR partial agonists has become an important research focus. In this study, we report on LUF7746, a capadenoson derivative bearing an electrophilic fluorosulfonyl moiety, as an irreversibly binding hA1AR modulator. Meanwhile, a nonreactive ligand bearing a methylsulfonyl moiety, LUF7747, was designed as a control probe in our study. In a radioligand binding assay, LUF7746’s apparent affinity increased to nanomolar range with longer pre-incubation time, suggesting an increasing level of covalent binding over time. Moreover, compared to the reference full agonist CPA, LUF7746 was a partial agonist in a hA1AR-mediated G protein activation assay and resistant to blockade with an antagonist/inverse agonist. An in silico structure-based docking study combined with site-directed mutagenesis of the hA1AR demonstrated that amino acid Y2717.36 was the primary anchor point for the covalent interaction. Additionally, a label-free whole-cell assay was set up to identify LUF7746’s irreversible activation of an A1 receptor-mediated cell morphological response. These results led us to conclude that LUF7746 is a novel covalent hA1AR partial agonist and a valuable chemical probe for further mapping the receptor activation process. It may also serve as a prototype for a therapeutic approach in which a covalent partial agonist may cause less on-target side effects, conferring enhanced safety compared to a full agonist.
Development of Covalent, Clickable Probes for Adenosine A1and A3Receptors
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.
supporting information, p. 8161 - 8178 (2021/06/30)
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 A1receptor (A1R) and adenosine A3receptor (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 A2Aand A2Badenosine 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.
