Adenosine A1 receptors (A1R) are a potential target for cardiac injury treatment due to their cardioprotective/antihypertrophic actions, but
drug development has been hampered by on-target side effects such as
bradycardia and altered renal hemodynamics. Biased agonism has emerged as an attractive mechanism for A1R-mediated cardioprotection that is haemodynamically safe. Here we investigate the pre-clinical pharmacology, efficacy and side-effect profile of the A1R agonist neladenoson, shown to be safe but ineffective in phase IIb trials for the treatment of
heart failure. We compare this agent with the well-characterized, pan-
adenosine receptor (AR) agonist
NECA,
capadenoson, and the A1R biased agonist
VCP746, previously shown to be safe and cardioprotective in pre-clinical models of
heart failure. We show that like
VCP746, neladenoson is biased away from Ca2+ influx relative to
NECA and the cAMP pathway at the A1R, a profile predictive of a lack of
adenosine-like side effects. Additionally, neladenoson was also biased away from the MAPK pathway at the A1R. In contrast to
VCP746, which displays more '
adenosine-like' signaling at the A2BR, neladenoson was a highly selective A1R agonist, with biased, weak agonism at the A2BR. Together these results show that unwanted hemodynamic effects of A1R agonists can be avoided by compounds biased away from Ca2+ influx relative to cAMP, relative to
NECA. The failure of neladenoson to reach primary endpoints in clinical trials suggests that A1R-mediated cAMP inhibition may be a poor
indicator of effectiveness in chronic
heart failure. This study provides additional information that can aid future screening and/or design of improved AR agonists that are safe and efficacious in treating
heart failure in patients.