Capadenoson, a clinically trialed partial adenosine A1receptor agonist, can stimulate adenosine A2Breceptor biased agonism.
The adenosine A2Breceptor (A2BAR) has been identified as an important therapeutic target in cardiovascular disease, however in vitro and in vivo targeting has been limited by the paucity of pharmacological tools, particularly potent agonists. Interestingly, 2-((6-amino-3,5-dicyano-4-(4-(cyclopropylmethoxy)phenyl)-2-pyridinyl)thio)acetamide (BAY60-6583), a potent and subtype-selective A2BAR agonist, has the same core structure as 2-amino-6-[[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methylsulfanyl]-4-[4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitril (capadenoson). Capadenoson, currently classified as an adenosine A1receptor (A1AR) partial agonist, has undergone two Phase IIa clinical trials, initially in patients with atrial fibrillation and subsequently in patients with stable angina. Capadenoson has also been shown to decrease cardiac remodeling in an animal model of advanced heart failure and a capadenoson derivative, neladenoson bialanate, recently entered clinical development for the treatment of chronic heart failure. The therapeutic effects of capadenoson are currently thought to be mediated through the A1AR. However, the ability of capadenoson to stimulate additional adenosine receptor subtypes, in particular the A2BAR, has not been rigorously assessed. In this study, we demonstrate that capadenoson does indeed have significant A2BAR activity in physiologically relevant cells, cardiac fibroblasts and cardiomyocytes, which endogenously express the A2BAR. Relative to the non-selective adenosine receptor agonist NECA, capadenoson was a biased A2BAR agonist with a preference for cAMP signal transduction over other downstream mediators in cells with recombinant and endogenous A2BAR expression. These findings suggest the reclassification of capadenoson as a dual A1AR/A2BAR agonist. Furthermore, a potential A2BAR contribution should be an important consideration for the future clinical development of capadenoson-like therapeutics, as the A2BAR can promote cardioprotection and modulate cardiac fibrosis in heart disease.
Drug Discovery Biology & Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
Jo-Anne
JA
Baltos
Drug Discovery Biology & Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
Elizabeth A
EA
Vecchio
Drug Discovery Biology & Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
Matthew A
MA
Harris
Heart Failure Pharmacology, Baker IDI Heart & Diabetes Institute, Melbourne, VIC 3004, Australia.
Cheng Xue
CX
Qin
Heart Failure Pharmacology, Baker IDI Heart & Diabetes Institute, Melbourne, VIC 3004, Australia.
Rebecca H
RH
Ritchie
Drug Discovery Biology & Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
Arthur
A
Christopoulos
Drug Discovery Biology & Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
Paul J
PJ
White
Drug Discovery Biology & Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia. Electronic address: lauren.may@monash.edu.
Lauren T
LT
May
D058907:Adenosine A1 Receptor Agonists / Q000494:pharmacology*; D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology*; D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D054333:Drug Partial Agonism; D057809:HEK293 Cells; D006801:Humans; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D017207:Rats, Sprague-Dawley; D043682:Receptor, Adenosine A1 / Q000502:physiology*; D043704:Receptor, Adenosine A2B / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology*
D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D000631:Aminopyridines; D043682:Receptor, Adenosine A1; D043704:Receptor, Adenosine A2B; D013844:Thiazoles; C575871:capadenoson
Adenosine A(2B) receptor; BAY60-6583 (PubChem CID: 11717831); Biased agonist; Capadenoson; Capadenoson (PubChem CID: 9936489); Cardiac fibroblasts; Cardiomyocytes; NECA (PubChem CID: 448222); PSB-603 (PubChem CID: 44185871); SCH442416 (PubChem CID: 10668061); SLV320 (PubChem CID: 9953065); [(3)H]DPCPX (PubChem CID: 53319341)