Comparative evaluation of biased agonists Sarcosine(1), d‐Alanine (8) ‐Angiotensin (Ang) II (SD Ang II) and Sarcosine(1), Isoleucine (8) ‐Ang II (SI Ang II) and their radioiodinated congeners binding to rat liver membrane AT(1) receptors

Angiotensin II analogue and β‐arrestin biased agonist TRV027 (Sarcosine(1), d‐Alanine(8)‐Angiotensin (Ang) II; SD Ang II), developed by Trevena, Inc. in the early 2010s, brought hopes of a novel treatment for cardiovascular diseases, due to its ability to simultaneously cause signaling through the β‐arrestin signaling pathway, while antagonizing the pathophysiological effects of Ang II mediated by the AT(1) receptor G protein signaling cascades. However, a phase II clinical trial of this agent revealed no significant benefit compared to placebo treatment. Using (125)I‐Sarcosine(1), Isoleucine(8)‐Ang II ((125)I‐SI Ang II) radioligand receptor competition binding assays, we assessed the relative affinity of TRV027 compared to SI Ang II for liver AT(1) receptors. We also compared radioiodinated TRV027 ((125)I‐SD Ang II) binding affinity for liver AT(1) receptors with (125)I‐SI Ang II. We found that despite its anticipated gain in metabolic stability, TRV027 and (125)I‐SD Ang II had reduced affinity for the AT(1) receptor compared with SI Ang II and (125)I‐SI Ang II. Additionally, male–female comparisons showed that females have a higher AT(1) receptor density, potentially attributed to tissue‐dependent 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®'s biased agonist peptide TRV027 offered greater stability and potency compared to earlier AT(1)R biased agonists, it failed its phase II clinical trial in 2016. Further refinements to AT(1)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.