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Adenosine A1 Receptor Biased Agonism: A Novel Approach for Cardioprotective Therapeutics
Author(s) -
May Lauren Therese,
Baltos JoAnne,
White Paul J,
Valant Celine,
Scammells Peter J,
Sexton Patrick M,
Christopoulos Arthur
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.lb617
Subject(s) - cardioprotection , adenosine , pharmacology , functional selectivity , adenosine receptor , agonism , bradycardia , g protein coupled receptor , medicine , receptor , heart rate , agonist , chemistry , blood pressure , ischemia , politics , political science , law
Adenosine receptor (AR) activation represents the most powerful cardioprotective mechanism. Unfortunately, the translation of A 1 AR agonists into the clinic has been severely hindered due to on‐target adverse effects, including bradycardia, atrioventricular block and hypotension. GPCR biased agonism represents an exciting approach to develop adenosine therapeutics that selectively enhance cardioprotective signaling in the absence of unwanted effects. This study used a chemical biology approach and novel analytical methods to identify and profile physiologically relevant A 1 AR biased agonists. The reference A 1 AR agonists, NECA and R‐PIA, did not display significant bias for any of the signaling pathways assessed; whereas VCP746 was significantly biased away from calcium mobilization. VCP746 mediated potent cardioprotection with minimal effects on heart rate or blood pressure; enabling, for the first time, separation of desired from adverse effects. Collectively, these studies demonstrate that “fingerprinting” of biased agonism within a model system can be predictive of novel and physiologically relevant in vivo pharmacology. This research was supported by the NHMRC.