A Structure-Activity Relationship Study of Bitopic N 6-Substituted Adenosine Derivatives as Biased Adenosine A1 Receptor Agonists

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Abstract

The adenosine A1 receptor (A1AR) is a potential novel therapeutic target for myocardial ischemia-reperfusion injury. However, to date, clinical translation of prototypical A1AR agonists has been hindered due to dose limiting adverse effects. Recently, we demonstrated that the biased bitopic agonist 1, consisting of an adenosine pharmacophore linked to an allosteric moiety, could stimulate cardioprotective A1AR signaling in the absence of unwanted bradycardia. Therefore, this study aimed to investigate the structure-activity relationship of compound 1 biased agonism. A series of novel derivatives of 1 were synthesized and pharmacologically profiled. Modifications were made to the orthosteric adenosine pharmacophore, linker, and allosteric 2-amino-3-benzoylthiophene pharmacophore to probe the structure-activity relationships, particularly in terms of biased signaling, as well as A1AR activity and subtype selectivity. Collectively, our findings demonstrate that the allosteric moiety, particularly the 4-(trifluoromethyl)phenyl substituent of the thiophene scaffold, is important in conferring bitopic ligand bias at the A1AR.

Original languageEnglish
Pages (from-to)2087-2103
Number of pages17
JournalJournal of Medicinal Chemistry
Volume61
Issue number5
DOIs
Publication statusPublished - 8 Mar 2018

Cite this

@article{e3b537a225ea4f44b29f459394c52b07,
title = "A Structure-Activity Relationship Study of Bitopic N 6-Substituted Adenosine Derivatives as Biased Adenosine A1 Receptor Agonists",
abstract = "The adenosine A1 receptor (A1AR) is a potential novel therapeutic target for myocardial ischemia-reperfusion injury. However, to date, clinical translation of prototypical A1AR agonists has been hindered due to dose limiting adverse effects. Recently, we demonstrated that the biased bitopic agonist 1, consisting of an adenosine pharmacophore linked to an allosteric moiety, could stimulate cardioprotective A1AR signaling in the absence of unwanted bradycardia. Therefore, this study aimed to investigate the structure-activity relationship of compound 1 biased agonism. A series of novel derivatives of 1 were synthesized and pharmacologically profiled. Modifications were made to the orthosteric adenosine pharmacophore, linker, and allosteric 2-amino-3-benzoylthiophene pharmacophore to probe the structure-activity relationships, particularly in terms of biased signaling, as well as A1AR activity and subtype selectivity. Collectively, our findings demonstrate that the allosteric moiety, particularly the 4-(trifluoromethyl)phenyl substituent of the thiophene scaffold, is important in conferring bitopic ligand bias at the A1AR.",
author = "Luigi Aurelio and Baltos, {Jo Anne} and Leigh Ford and Nguyen, {Anh T.N.} and Manuela J{\"o}rg and Devine, {Shane M.} and Celine Valant and White, {Paul J.} and Arthur Christopoulos and May, {Lauren T.} and Scammells, {Peter J.}",
year = "2018",
month = "3",
day = "8",
doi = "10.1021/acs.jmedchem.8b00047",
language = "English",
volume = "61",
pages = "2087--2103",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "AMER CHEMICAL SOC",
number = "5",

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TY - JOUR

T1 - A Structure-Activity Relationship Study of Bitopic N 6-Substituted Adenosine Derivatives as Biased Adenosine A1 Receptor Agonists

AU - Aurelio, Luigi

AU - Baltos, Jo Anne

AU - Ford, Leigh

AU - Nguyen, Anh T.N.

AU - Jörg, Manuela

AU - Devine, Shane M.

AU - Valant, Celine

AU - White, Paul J.

AU - Christopoulos, Arthur

AU - May, Lauren T.

AU - Scammells, Peter J.

PY - 2018/3/8

Y1 - 2018/3/8

N2 - The adenosine A1 receptor (A1AR) is a potential novel therapeutic target for myocardial ischemia-reperfusion injury. However, to date, clinical translation of prototypical A1AR agonists has been hindered due to dose limiting adverse effects. Recently, we demonstrated that the biased bitopic agonist 1, consisting of an adenosine pharmacophore linked to an allosteric moiety, could stimulate cardioprotective A1AR signaling in the absence of unwanted bradycardia. Therefore, this study aimed to investigate the structure-activity relationship of compound 1 biased agonism. A series of novel derivatives of 1 were synthesized and pharmacologically profiled. Modifications were made to the orthosteric adenosine pharmacophore, linker, and allosteric 2-amino-3-benzoylthiophene pharmacophore to probe the structure-activity relationships, particularly in terms of biased signaling, as well as A1AR activity and subtype selectivity. Collectively, our findings demonstrate that the allosteric moiety, particularly the 4-(trifluoromethyl)phenyl substituent of the thiophene scaffold, is important in conferring bitopic ligand bias at the A1AR.

AB - The adenosine A1 receptor (A1AR) is a potential novel therapeutic target for myocardial ischemia-reperfusion injury. However, to date, clinical translation of prototypical A1AR agonists has been hindered due to dose limiting adverse effects. Recently, we demonstrated that the biased bitopic agonist 1, consisting of an adenosine pharmacophore linked to an allosteric moiety, could stimulate cardioprotective A1AR signaling in the absence of unwanted bradycardia. Therefore, this study aimed to investigate the structure-activity relationship of compound 1 biased agonism. A series of novel derivatives of 1 were synthesized and pharmacologically profiled. Modifications were made to the orthosteric adenosine pharmacophore, linker, and allosteric 2-amino-3-benzoylthiophene pharmacophore to probe the structure-activity relationships, particularly in terms of biased signaling, as well as A1AR activity and subtype selectivity. Collectively, our findings demonstrate that the allosteric moiety, particularly the 4-(trifluoromethyl)phenyl substituent of the thiophene scaffold, is important in conferring bitopic ligand bias at the A1AR.

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U2 - 10.1021/acs.jmedchem.8b00047

DO - 10.1021/acs.jmedchem.8b00047

M3 - Article

VL - 61

SP - 2087

EP - 2103

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 5

ER -