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 language | English |
|---|---|
| Pages (from-to) | 2087-2103 |
| Number of pages | 17 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 61 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 8 Mar 2018 |
Cite this
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A Structure-Activity Relationship Study of Bitopic N 6-Substituted Adenosine Derivatives as Biased Adenosine A1 Receptor Agonists. / Aurelio, Luigi; Baltos, Jo Anne; Ford, Leigh; Nguyen, Anh T.N.; Jörg, Manuela; Devine, Shane M.; Valant, Celine; White, Paul J.; Christopoulos, Arthur; May, Lauren T.; Scammells, Peter J.
In: Journal of Medicinal Chemistry, Vol. 61, No. 5, 08.03.2018, p. 2087-2103.Research output: Contribution to journal › Article › Research › peer-review
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.
UR - http://www.scopus.com/inward/record.url?scp=85043451134&partnerID=8YFLogxK
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 -