Novel irreversible agonists acting at the A1 adenosine receptor

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The A1 adenosine 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.

Original languageEnglish
Pages (from-to)11182-11194
Number of pages13
JournalJournal of Medicinal Chemistry
Volume59
Issue number24
DOIs
Publication statusPublished - 22 Dec 2016

Cite this

@article{985b4c8d2c72421cb9b860dc749a0b99,
title = "Novel irreversible agonists acting at the A1 adenosine receptor",
abstract = "The A1 adenosine 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.",
author = "Manuela Jorg and Alisa Glukhova and {Abdul Ridha}, Alaa and Vecchio, {Elizabeth A.} and Anh Nguyen and Patrick Sexton and Paul White and Lauren May and Arthur Christopoulos and Peter Scammells",
year = "2016",
month = "12",
day = "22",
doi = "10.1021/acs.jmedchem.6b01561",
language = "English",
volume = "59",
pages = "11182--11194",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "AMER CHEMICAL SOC",
number = "24",

}

Novel irreversible agonists acting at the A1 adenosine receptor. / Jorg, Manuela; Glukhova, Alisa; Abdul Ridha, Alaa; Vecchio, Elizabeth A.; Nguyen, Anh; Sexton, Patrick; White, Paul; May, Lauren; Christopoulos, Arthur; Scammells, Peter.

In: Journal of Medicinal Chemistry, Vol. 59, No. 24, 22.12.2016, p. 11182-11194.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Novel irreversible agonists acting at the A1 adenosine receptor

AU - Jorg, Manuela

AU - Glukhova, Alisa

AU - Abdul Ridha, Alaa

AU - Vecchio, Elizabeth A.

AU - Nguyen, Anh

AU - Sexton, Patrick

AU - White, Paul

AU - May, Lauren

AU - Christopoulos, Arthur

AU - Scammells, Peter

PY - 2016/12/22

Y1 - 2016/12/22

N2 - The A1 adenosine 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.

AB - The A1 adenosine 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.

UR - http://www.scopus.com/inward/record.url?scp=85007170361&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.6b01561

DO - 10.1021/acs.jmedchem.6b01561

M3 - Article

VL - 59

SP - 11182

EP - 11194

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 24

ER -