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However, a phase II clinical trial of this agent revealed no significant benefit compared to placebo treatment. Using <jats:sup>125<\/jats:sup>I\u2010Sarcosine<jats:sup>1<\/jats:sup>, Isoleucine<jats:sup>8<\/jats:sup>\u2010Ang II (<jats:sup>125<\/jats:sup>I\u2010SI Ang II) radioligand receptor competition binding assays, we assessed the relative affinity of TRV027 compared to SI Ang II for liver AT<jats:sub>1<\/jats:sub> receptors. We also compared radioiodinated TRV027 (<jats:sup>125<\/jats:sup>I\u2010SD Ang II) binding affinity for liver AT<jats:sub>1<\/jats:sub> receptors with <jats:sup>125<\/jats:sup>I\u2010SI Ang II. We found that despite its anticipated gain in metabolic stability, TRV027 and <jats:sup>125<\/jats:sup>I\u2010SD Ang II had reduced affinity for the AT<jats:sub>1<\/jats:sub> receptor compared with SI Ang II and <jats:sup>125<\/jats:sup>I\u2010SI Ang II. Additionally, male\u2013female comparisons showed that females have a higher AT<jats:sub>1<\/jats:sub> receptor density, potentially attributed to tissue\u2010dependent estrogen and progesterone effects. Peptide drugs have become more popular over the years due to their increased bioavailability, fast onset of action, high specificity, and low toxicity. Even though Trevena\u00ae's biased agonist peptide TRV027 offered greater stability and potency compared to earlier AT<jats:sub>1<\/jats:sub>R biased agonists, it failed its phase II clinical trial in 2016. Further refinements to AT<jats:sub>1<\/jats:sub>R biased agonist peptides to improve affinity, as seen with SI Ang II, with better stability and bioavailability, has the potential to achieve the anticipated biased agonism.<\/jats:p>","DOI":"10.1002\/prp2.1053","type":"journal-article","created":{"date-parts":[[2023,1,14]],"date-time":"2023-01-14T08:22:23Z","timestamp":1673684543000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Comparative evaluation of biased agonists Sarcosine<sup>1<\/sup>, <scp>d<\/scp>\u2010<scp>A<\/scp>lanine<scp><sup>8<\/sup><\/scp>\u2010<scp>A<\/scp>ngiotensin (Ang) <scp>II<\/scp> (<scp>SD<\/scp> Ang <scp>II<\/scp>) and Sarcosine<sup>1<\/sup>, <scp>I<\/scp>soleucine<scp><sup>8<\/sup><\/scp>\u2010<scp>A<\/scp>ng <scp>II<\/scp> (<scp>SI<\/scp> Ang <scp>II<\/scp>) and their radioiodinated congeners binding to rat liver membrane <scp>AT<sub>1<\/sub><\/scp> receptors"],"prefix":"10.1002","volume":"11","author":[{"given":"Natalia M.","family":"Noto","sequence":"first","affiliation":[{"name":"College of Pharmacy Nova Southeastern University  Fort Lauderdale Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yazmin M.","family":"Restrepo","sequence":"additional","affiliation":[{"name":"College of Pharmacy Nova Southeastern University  Fort Lauderdale Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong W.","family":"Pang","sequence":"additional","affiliation":[{"name":"College of Pharmacy Nova Southeastern University  Fort Lauderdale Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Filipe","family":"Stoyell\u2010Conti","sequence":"additional","affiliation":[{"name":"College of Pharmacy Nova Southeastern University  Fort Lauderdale Florida USA"},{"name":"University of Miami  Miami Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Crystal A.","family":"West","sequence":"additional","affiliation":[{"name":"Department of Biology Appalachian State University  Kannapolis North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6434-2136","authenticated-orcid":false,"given":"Robert C.","family":"Speth","sequence":"additional","affiliation":[{"name":"College of Pharmacy Nova Southeastern University  Fort Lauderdale Florida USA"},{"name":"Department of Pharmacology and Physiology, College of Medicine Georgetown University  Washington District of Columbia 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