342878-90-4Relevant articles and documents
Functional Selectivity Revealed by N-Methylation Scanning of Human Urotensin II and Related Peptides
Merlino, Francesco,Billard, étienne,Yousif, Ali M.,Di Maro, Salvatore,Brancaccio, Diego,Abate, Luigi,Carotenuto, Alfonso,Bellavita, Rosa,D'Emmanuele Di Villa Bianca, Roberta,Santicioli, Paolo,Marinelli, Luciana,Novellino, Ettore,Hébert, Terence E.,Lubell, William D.,Chatenet, David,Grieco, Paolo
, p. 1455 - 1467 (2019)
In accordance with their common but also divergent physiological actions, human urotensin II (1) and urotensin II-related peptide (2) could stabilize specific urotensin II receptor (UTR) conformations, thereby activating different signaling pathways, a feature referred to as biased agonism or functional selectivity. Sequential N-methylation of the amides in the conserved core sequence of 1, 2, and fragment U-II4-11 (3) shed light on structural requirements involved in their functional selectivity. Thus, 18 N-methylated UTR ligands were synthesized and their biological profiles evaluated using in vitro competition binding assays, ex vivo rat aortic ring bioassays and BRET-based biosensor experiments. Biological activity diverged from that of the parent structures contingent on the location of amide methylation, indicating relevant hydrogen-bond interactions for the function of the endogenous peptides. Conformational analysis of selected N-methyl analogs indicated the importance of specific amide residues of 2 for the distinct pharmacology relative to 1 and 3.
An investigation into the origin of the biased agonism associated with the urotensin II receptor activation
Brancaccio, Diego,Merlino, Francesco,Limatola, Antonio,Yousif, Ali Munaim,Gomez-Monterrey, Isabel,Campiglia, Pietro,Novellino, Ettore,Grieco, Paolo,Carotenuto, Alfonso
, p. 392 - 399 (2015/05/13)
The urotensin II receptor (UTR) has long been studied mainly for its involvement in the cardiovascular homeostasis both in health and disease state. Two endogenous ligands activate UTR, i.e. urotensin II (U-II) and urotensin II-related peptide (URP). Exte