6hvb

Publication Abstract from PubMed

In accordance with their common but also divergent physiological actions, human urotensin II ( hU-II, 1) and urotensin II-related peptide (URP, 2) could stabilize specific urotensin II receptor (UTR) conformations, thereby activating different signalling 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, eighteen N-methylated UTR ligands were synthesized and their biological profiles evaluated using both 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 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.

Functional Selectivity Revealed by N-Methylation Scanning of Human Urotensin II and Related Peptides.,Merlino F, Billard E, Yousif AM, Di Maro S, Brancaccio D, Abate L, Carotenuto A, Bellavita R, d'Emmanuele di Villa Bianca R, Santicioli P, Marinelli L, Novellino E, Hebert T, Lubell WD, Chatenet D, Grieco P J Med Chem. 2019 Jan 7. doi: 10.1021/acs.jmedchem.8b01601. PMID:30615452^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.