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• W3044454921 abstract "ABSTRACT Adenosine A 1 receptors (A 1 R) 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 haemodynamics. Biased agonism has emerged as an attractive mechanism for A 1 R-mediated cardioprotection that is haemodynamically safe. Here we investigate the pre-clinical pharmacology, efficacy and side-effect profile of the A 1 R 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-characterised, pan-adenosine receptor (AR) agonist NECA, capadenoson, and the A 1 R 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 Ca 2+ influx relative to NECA and the cAMP pathway at the A 1 R, a profile predictive of a lack of adenosine-like side effects. Additionally, neladenoson was also biased away from the MAPK pathway at the A 1 R. In contrast to VCP746, which displays more ‘adenosine-like’ signalling at the A 2B R, neladenoson was a highly selective A 1 R agonist, with biased, weak agonism at the A 2B R. Together these results show that unwanted haemodynamic effects of A 1 R agonists can be avoided by compounds biased away from Ca 2+ influx relative to cAMP, relative to NECA. The failure of neladenoson to reach primary endpoints in clinical trials suggests that A 1 R-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. ONE-SENTENCE SUMMARY Biased agonists that preference against calcium influx relative to the cyclic AMP pathway, when compared to a conventional agonist, confer clinical safety to A 1 adenosine receptor ligands." @default.
• W3044454921 created "2020-07-29" @default.
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• W3044454921 date "2020-07-23" @default.
• W3044454921 modified "2023-09-25" @default.
• W3044454921 title "Pharmacological insights into safety and efficacy determinants for the development of adenosine receptor biased agonists in the treatment of heart failure" @default.
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• W3044454921 doi "https://doi.org/10.1101/2020.07.22.215509" @default.
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