Structure-activity analysis of biased agonism at the human adenosine A3 receptor

Jo-Anne Baltos, Silvia Paoletta, Anh T. N. Nguyen, Karen J. Gregory, Dilip K. Tosh, Arthur Christopoulos, Kenneth A. Jacobson, Lauren T. May

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Biased agonism at G protein-coupled receptors (GPCRs) has significant implications for current drug discovery, but molecular determinants that govern ligand bias remain largely unknown. The adenosine A3 GPCR (A3AR) is a potential therapeutic target for various conditions, including cancer, inflammation, and ischemia, but for which biased agonism remains largely unexplored. We now report the generation of bias "fingerprints" for prototypical ribose containing A3AR agonists and rigidified (N)-methanocarba 59-N-methyluronamide nucleoside derivatives with regard to their ability to mediate different signaling pathways. Relative to the reference prototypical agonist IB-MECA, (N)-methanocarba 59-Nmethyluronamide nucleoside derivatives with significant N6 or C2 modifications, including elongated aryl-ethynyl groups, exhibited biased agonism. Significant positive correlation was observed between the C2 substituent length (in Å) and bias toward cell survival. Molecular modeling suggests that extended C2 substituents on (N)-methanocarba 59-N-methyluronamide nucleosides promote a progressive outward shift of the A3AR transmembrane domain 2, which may contribute to the subset of A3AR conformations stabilized on biased agonist binding.

Original languageEnglish
Pages (from-to)12-22
Number of pages11
JournalMolecular Pharmacology
Volume90
Issue number1
DOIs
Publication statusPublished - 1 Jul 2016

Cite this

Baltos, Jo-Anne ; Paoletta, Silvia ; Nguyen, Anh T. N. ; Gregory, Karen J. ; Tosh, Dilip K. ; Christopoulos, Arthur ; Jacobson, Kenneth A. ; May, Lauren T. / Structure-activity analysis of biased agonism at the human adenosine A3 receptor. In: Molecular Pharmacology. 2016 ; Vol. 90, No. 1. pp. 12-22.
@article{40672eff8ea24154a271c74d0ac7e172,
title = "Structure-activity analysis of biased agonism at the human adenosine A3 receptor",
abstract = "Biased agonism at G protein-coupled receptors (GPCRs) has significant implications for current drug discovery, but molecular determinants that govern ligand bias remain largely unknown. The adenosine A3 GPCR (A3AR) is a potential therapeutic target for various conditions, including cancer, inflammation, and ischemia, but for which biased agonism remains largely unexplored. We now report the generation of bias {"}fingerprints{"} for prototypical ribose containing A3AR agonists and rigidified (N)-methanocarba 59-N-methyluronamide nucleoside derivatives with regard to their ability to mediate different signaling pathways. Relative to the reference prototypical agonist IB-MECA, (N)-methanocarba 59-Nmethyluronamide nucleoside derivatives with significant N6 or C2 modifications, including elongated aryl-ethynyl groups, exhibited biased agonism. Significant positive correlation was observed between the C2 substituent length (in {\AA}) and bias toward cell survival. Molecular modeling suggests that extended C2 substituents on (N)-methanocarba 59-N-methyluronamide nucleosides promote a progressive outward shift of the A3AR transmembrane domain 2, which may contribute to the subset of A3AR conformations stabilized on biased agonist binding.",
author = "Jo-Anne Baltos and Silvia Paoletta and Nguyen, {Anh T. N.} and Gregory, {Karen J.} and Tosh, {Dilip K.} and Arthur Christopoulos and Jacobson, {Kenneth A.} and May, {Lauren T.}",
year = "2016",
month = "7",
day = "1",
doi = "10.1124/mol.116.103283",
language = "English",
volume = "90",
pages = "12--22",
journal = "Molecular Pharmacology",
issn = "1521-0111",
publisher = "ACS Books",
number = "1",

}

Structure-activity analysis of biased agonism at the human adenosine A3 receptor. / Baltos, Jo-Anne; Paoletta, Silvia; Nguyen, Anh T. N.; Gregory, Karen J.; Tosh, Dilip K.; Christopoulos, Arthur; Jacobson, Kenneth A.; May, Lauren T.

In: Molecular Pharmacology, Vol. 90, No. 1, 01.07.2016, p. 12-22.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Structure-activity analysis of biased agonism at the human adenosine A3 receptor

AU - Baltos, Jo-Anne

AU - Paoletta, Silvia

AU - Nguyen, Anh T. N.

AU - Gregory, Karen J.

AU - Tosh, Dilip K.

AU - Christopoulos, Arthur

AU - Jacobson, Kenneth A.

AU - May, Lauren T.

PY - 2016/7/1

Y1 - 2016/7/1

N2 - Biased agonism at G protein-coupled receptors (GPCRs) has significant implications for current drug discovery, but molecular determinants that govern ligand bias remain largely unknown. The adenosine A3 GPCR (A3AR) is a potential therapeutic target for various conditions, including cancer, inflammation, and ischemia, but for which biased agonism remains largely unexplored. We now report the generation of bias "fingerprints" for prototypical ribose containing A3AR agonists and rigidified (N)-methanocarba 59-N-methyluronamide nucleoside derivatives with regard to their ability to mediate different signaling pathways. Relative to the reference prototypical agonist IB-MECA, (N)-methanocarba 59-Nmethyluronamide nucleoside derivatives with significant N6 or C2 modifications, including elongated aryl-ethynyl groups, exhibited biased agonism. Significant positive correlation was observed between the C2 substituent length (in Å) and bias toward cell survival. Molecular modeling suggests that extended C2 substituents on (N)-methanocarba 59-N-methyluronamide nucleosides promote a progressive outward shift of the A3AR transmembrane domain 2, which may contribute to the subset of A3AR conformations stabilized on biased agonist binding.

AB - Biased agonism at G protein-coupled receptors (GPCRs) has significant implications for current drug discovery, but molecular determinants that govern ligand bias remain largely unknown. The adenosine A3 GPCR (A3AR) is a potential therapeutic target for various conditions, including cancer, inflammation, and ischemia, but for which biased agonism remains largely unexplored. We now report the generation of bias "fingerprints" for prototypical ribose containing A3AR agonists and rigidified (N)-methanocarba 59-N-methyluronamide nucleoside derivatives with regard to their ability to mediate different signaling pathways. Relative to the reference prototypical agonist IB-MECA, (N)-methanocarba 59-Nmethyluronamide nucleoside derivatives with significant N6 or C2 modifications, including elongated aryl-ethynyl groups, exhibited biased agonism. Significant positive correlation was observed between the C2 substituent length (in Å) and bias toward cell survival. Molecular modeling suggests that extended C2 substituents on (N)-methanocarba 59-N-methyluronamide nucleosides promote a progressive outward shift of the A3AR transmembrane domain 2, which may contribute to the subset of A3AR conformations stabilized on biased agonist binding.

UR - http://www.scopus.com/inward/record.url?scp=84976440477&partnerID=8YFLogxK

U2 - 10.1124/mol.116.103283

DO - 10.1124/mol.116.103283

M3 - Article

VL - 90

SP - 12

EP - 22

JO - Molecular Pharmacology

JF - Molecular Pharmacology

SN - 1521-0111

IS - 1

ER -