Wei, Xiaozheng; Diarra, Sitan; Douchez, Antoine; Dallagnol, Juliana C; Hébert, Terence E; Chatenet, David 
ORCID: 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.
Résumé
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 |
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