Capadenoson, a clinically trialed partial adenosine A1 receptor agonist, can stimulate adenosine A2B receptor biased agonism

The adenosine A_2B receptor (A_2BAR) 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 A_2BAR 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 A₁ receptor (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 A_2BAR, has not been rigorously assessed. In this study, we demonstrate that capadenoson does indeed have significant A_2BAR activity in physiologically relevant cells, cardiac fibroblasts and cardiomyocytes, which endogenously express the A_2BAR. Relative to the non-selective Adenosine Receptor agonist NECA, capadenoson was a biased A_2BAR agonist with a preference for cAMP signal transduction over other downstream mediators in cells with recombinant and endogenous A_2BAR expression. These findings suggest the reclassification of capadenoson as a dual A₁AR/A_2BAR agonist. Furthermore, a potential A_2BAR contribution should be an important consideration for the future clinical development of capadenoson-like therapeutics, as the A_2BAR can promote cardioprotection and modulate cardiac fibrosis in heart disease.