Functional Selectivity Revealed by N-Methylation Scanning of Human Urotensin II and Related Peptides

Abstract : 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.
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Submitted on : Tuesday, May 21, 2019 - 6:03:17 PM
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Francesco Merlino, Étienne Billard, Ali Yousif, Salvatore Di Maro, Diego Brancaccio, et al.. Functional Selectivity Revealed by N-Methylation Scanning of Human Urotensin II and Related Peptides. Journal of Medicinal Chemistry, American Chemical Society, 2019, 62 (3), pp.1455-1467. ⟨10.1021/acs.jmedchem.8b01601⟩. ⟨pasteur-02136107⟩

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