%0 Journal Article %T Functional Selectivity Revealed by N-Methylation Scanning of Human Urotensin II and Related Peptides %+ University of Naples Federico II = Università degli studi di Napoli Federico II %+ Institut Armand Frappier (INRS-IAF) %+ Menarini Ricerche [Florence] %+ McGill University = Université McGill [Montréal, Canada] %+ Université de Montréal (UdeM) %A Merlino, Francesco %A Billard, Étienne %A Yousif, Ali, M. %A Di Maro, Salvatore %A Brancaccio, Diego %A Abate, Luigi %A Carotenuto, Alfonso %A Bellavita, Rosa %A d'Emmanuele Di Villa Bianca, Roberta %A Santicioli, Paolo %A Marinelli, Luciana %A Novellino, Ettore %A Hébert, Terence, E. %A Lubell, William, D. %A Chatenet, David %A Grieco, Paolo %Z The study was supported by Canadian Institutes of Health Research (CIHR) (MOP-142184) and the Natural Sciences and Engineering Research Council of Canada (NSERC) (RGPIN-2015-04848) to D.C. We thank the Canadian Institutes of Health Research (CIHR) and the Natural Sciences and Engineering Research Council of Canada (NSERC) for funding %< avec comité de lecture %@ 0022-2623 %J Journal of Medicinal Chemistry %I American Chemical Society %V 62 %N 3 %P 1455-1467 %8 2019-07-01 %D 2019 %R 10.1021/acs.jmedchem.8b01601 %M 30615452 %Z Life Sciences [q-bio]Journal articles %X 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. %G English %L pasteur-02136107 %U https://riip.hal.science/pasteur-02136107 %~ RIIP %~ INRS-IAF