The Cardioprotective and Anti-Remodelling Effects of VCP746, a Novel A1/A2B Adenosine Receptor Agonist

Ischaemic heart disease, in particular myocardial infarction and resultant heart failure, places a significant burden on society. The adenosine receptor is a potent mediator of cardioprotection. Adenosine receptor signalling within cardiomyocytes during ischaemia and reperfusion injury reduces infarct size and improves post-ischemic heart function. However, the transition of adenosine receptor agonists into the clinic as a cardioprotective therapy has been hampered by significant on-target side effects such as bradycardia, atrioventricular block and hypotension. As such, while higher adenosine receptor agonist concentrations are likely to be more therapeutically effective, they cannot be trialled due to the likelihood of detrimental effects in patients with acute coronary occlusion. The failure of cardioprotective therapies in the clinic is also likely due to the relative inability of most drug candidates to control the remodelling process following myocardial infarction which leads to heart failure. VCP746, a novel A₁/A_2B adenosine receptor agonist, was previously shown to display biased agonism in Chinese hamster ovary cells stably expressing A1 adenosine receptors and furthermore, cytoprotection without bradycardia in native systems. A strong body of evidence also supports a role for adenosine receptor agonists in regulating cardiac remodelling processes such as cardiac hypertrophy and fibrosis. This project therefore aims to further explore the ability of VCP746 to confer cardioprotection in the absence of haemodynamic adverse effects in more physiologically relevant systems. In addition, the potential for VCP746 to reduce cardiac remodelling will also be investigated for the first time in cell-based and whole animal studies.