title: Novel Irreversible Agonists Acting at the A1Adenosine Receptor.
abstract: The A1adenosine receptor (A1AR) 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 A1AR, 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 A1AR. Of these compounds, 15b and 15d were more directly validated as irreversible agonists of the A1AR using membrane-based [3H]DPCPX and [35S]GTPγS binding experiments.
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria 3052, Australia.
authors.forename: Manuela
authors.initials: M
authors.lastname: Jörg
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences Biology, and Department of Pharmacology, Monash University , Parkville, Victoria 3052, Australia.
authors.forename: Alisa
authors.initials: A
authors.lastname: Glukhova
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences Biology, and Department of Pharmacology, Monash University , Parkville, Victoria 3052, Australia.
authors.forename: Alaa
authors.initials: A
authors.lastname: Abdul-Ridha
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences Biology, and Department of Pharmacology, Monash University , Parkville, Victoria 3052, Australia.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Vecchio
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences Biology, and Department of Pharmacology, Monash University , Parkville, Victoria 3052, Australia.
authors.forename: Anh T N
authors.initials: AT
authors.lastname: Nguyen
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences Biology, and Department of Pharmacology, Monash University , Parkville, Victoria 3052, Australia.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sexton
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences Biology, and Department of Pharmacology, Monash University , Parkville, Victoria 3052, Australia.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: White
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences Biology, and Department of Pharmacology, Monash University , Parkville, Victoria 3052, Australia.
authors.forename: Lauren T
authors.initials: LT
authors.lastname: May
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences Biology, and Department of Pharmacology, Monash University , Parkville, Victoria 3052, Australia.
authors.forename: Arthur
authors.initials: A
authors.lastname: Christopoulos
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria 3052, Australia.
authors.forename: Peter J
authors.identifier: 0000-0003-2930-895X
authors.initials: PJ
authors.lastname: Scammells
mesh_terms: D000241:Adenosine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D058907:Adenosine A1 Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D058907:Adenosine A1 Receptor Agonists; D043682:Receptor, Adenosine A1; D000241:Adenosine