Comparative evaluation of biased agonists Sarcosine1, d ‐Alanine8‐Angiotensin (Ang) II (SD Ang II) and Sarcosine1, Isoleucine8‐Ang II (SI Ang II) and their radioiodinated congeners binding to rat liver membrane AT1 receptors

Overview of outcomes resulting from action of full AT1R agonists versus biased AT1R agonists. AbstractAngiotensin II analogue and β-arrestin biased agonist TRV027 (Sarcosine1,d-Alanine8-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 AT1 receptor G protein signaling cascades. However, a phase II clinical trial of this agent revealed no significant benefit compared to placebo treatment. Using125I-Sarcosine1, Isoleucine8-Ang II (125I-SI Ang II) radioligand receptor competition binding assays, we assessed the relative affinity of TRV027 compared to SI Ang II for liver AT1 receptors. We also compared radioiodinated TRV027 (125I-SD Ang II) binding affinity for liver AT1 receptors with125I-SI Ang II. We found that despite its anticipated gain in metabolic stability, TRV027 and125I-SD Ang II had reduced affinity for the AT1 receptor compared with SI Ang II and125I-SI Ang II. Additionally, male –female comparisons showed that females have a higher AT1 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 ®...
Source: Pharmacology Research and Perspectives - Category: Drugs & Pharmacology Authors: Tags: ORIGINAL ARTICLE Source Type: research