Design and synthesis of novel AT1 receptor ligands: biochemical and pharmacological characterization in search of biased agonists (biased agonists)

Abstract

G protein-coupled receptors (GPCRs) are integral membrane proteins characterized by bearing seven transmembrane (TM) ±-helices, and for that they are also called 7TM receptors. This receptor superfamily mediates a large number of physiological processes and is target for approximately 40% of all drugs in the market. The angiotensin II type 1 (AT1) receptor is the major player of the renin-angiotensin system and is classically activated by the octapeptide angiotensin II (AngII). Recent reports have described agonists for distinct GPCRs, including the AT1 receptor, that can selectively (or at least preferentially) activate signaling pathways either dependent of G Protein or of b-arrestin coupling, and were therefore termed biased agonism. The goal of this project is to develop and characterize new ligands/drugs with selective agonistic activity for AT1 receptor, which then showing to possess pharmacological and functional relevance will enable future biotechnological applications. The purpose of this project is to perform the rational design of analogs of AngII, solid-phase synthesis, and biochemical and pharmacological characterization as the activity profile for different signaling pathways. We believe that the design of novel biased agonists may lead to development of a new generation of drugs, selective for activating not only a receptor subtype but also a specific signaling pathway. (AU)