{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T21:55:05Z","timestamp":1792274105773,"version":"4.4.0"},"reference-count":64,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,11]],"date-time":"2021-03-11T00:00:00Z","timestamp":1615420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    Adenosine A\n                    <jats:sub>1<\/jats:sub>\n                    receptors (A\n                    <jats:sub>1<\/jats:sub>\n                    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 hemodynamics. Biased agonism has emerged as an attractive mechanism for A\n                    <jats:sub>1<\/jats:sub>\n                    R-mediated cardioprotection that is haemodynamically safe. Here we investigate the pre-clinical pharmacology, efficacy and side-effect profile of the A\n                    <jats:sub>1<\/jats:sub>\n                    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-characterized, pan-adenosine receptor (AR) agonist NECA, capadenoson, and the A\n                    <jats:sub>1<\/jats:sub>\n                    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\n                    <jats:sup>2+<\/jats:sup>\n                    influx relative to NECA and the cAMP pathway at the A\n                    <jats:sub>1<\/jats:sub>\n                    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\n                    <jats:sub>1<\/jats:sub>\n                    R. In contrast to VCP746, which displays more \u2018adenosine-like\u2019 signaling at the A\n                    <jats:sub>2B<\/jats:sub>\n                    R, neladenoson was a highly selective A\n                    <jats:sub>1<\/jats:sub>\n                    R agonist, with biased, weak agonism at the A\n                    <jats:sub>2B<\/jats:sub>\n                    R. Together these results show that unwanted hemodynamic effects of A\n                    <jats:sub>1<\/jats:sub>\n                    R agonists can be avoided by compounds biased away from Ca\n                    <jats:sup>2+<\/jats:sup>\n                    influx relative to cAMP, relative to NECA. The failure of neladenoson to reach primary endpoints in clinical trials suggests that A\n                    <jats:sub>1<\/jats:sub>\n                    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.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2021.628060","type":"journal-article","created":{"date-parts":[[2021,3,11]],"date-time":"2021-03-11T01:18:59Z","timestamp":1615425539000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Pharmacological Insights Into Safety and Efficacy Determinants for the Development of Adenosine Receptor Biased Agonists in the Treatment of Heart Failure"],"prefix":"10.3389","volume":"12","author":[{"given":"Patricia","family":"Rueda","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon","family":"Merlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Chimenti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Feletou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerome","family":"Paysant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J.","family":"White","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur","family":"Christopoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick M.","family":"Sexton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger J.","family":"Summers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William N.","family":"Charman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren T.","family":"May","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Langmead","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1007\/s11302-011-9274-3","article-title":"Partial adenosine A1 receptor agonists for cardiovascular therapies","volume":"8","author":"Albrecht-K\u00fcpper","year":"2012","journal-title":"Purinergic Signal."},{"key":"B2","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1111\/j.1476-5381.1959.tb00928.x","article-title":"Some quantitative uses of drug antagonists","volume":"14","author":"Arunlakshana","year":"1959","journal-title":"Br. 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