Dépôt numérique

Urotensin II Receptor Modulation with 1,3,4-Benzotriazepin-2-one Tetrapeptide Mimics

Wei, Xiaozheng; Diarra, Sitan; Douchez, Antoine; Dallagnol, Juliana C; Hébert, Terence E; Chatenet, David ORCID logoORCID: https://orcid.org/0000-0002-7270-4328 et Lubell, William D (2023). Urotensin II Receptor Modulation with 1,3,4-Benzotriazepin-2-one Tetrapeptide Mimics Journal of Medicinal Chemistry , vol. 66 , nº 20. pp. 14241-14262. DOI: 10.1021/acs.jmedchem.3c01307.

Ce document n'est pas hébergé sur EspaceINRS.


Urotensin II receptor (UT) modulators that differentiate the effects of the endogenous cyclic peptide ligands urotensin II (UII) and urotensin II-related peptide (URP) offer potential for dissecting their respective biological roles in disease etiology. Selective modulators of hUII and URP activities were obtained using 1,3,4-benzotriazepin-2-one mimics of a purported bioactive γ-turn conformation about the Bip-Lys-Tyr tripeptide sequence of urocontrin ([Bip(4)]URP). Considering an active β-turn conformer about the shared Phe-Trp-Lys-Tyr sequence of UII and URP, 8-substituted 1,3,4-benzotriazepin-2-ones were designed to mimic the Phe-Bip-Lys-Tyr tetrapeptide sequence of urocontrin, synthesized, and examined for biological activity. Subtle 5- and 8-position modifications resulted in biased signaling and selective modulation of hUII- or URP-induced vasoconstriction. For example, p-hydroxyphenethyl analogs 17b-d were strong Gα(13) and βarr1 activators devoid of Gα(q)-mediated signaling. Tertiary amides 15d and 17d negatively modulated hUII-induced vasoconstriction without affecting URP-mediated responses. Benzotriazepinone carboxamides proved to be exceptional tools for elucidating the pharmacological complexity of UT.

Type de document: Article
Mots-clés libres: -
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 04 janv. 2024 14:46
Dernière modification: 04 janv. 2024 14:46
URI: https://espace.inrs.ca/id/eprint/13956

Gestion Actions (Identification requise)

Modifier la notice Modifier la notice