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Urotensin II(4-11) Azasulfuryl Peptides: Synthesis and Biological Activity

Merlino, Francesco; Yousif, Ali Munaim; Billard, Etienne; Dufour-Gallant, Julien; Turcotte, Stéphane; Grieco, Paolo; Chatenet, David; Lubell, William D. (2016). Urotensin II(4-11) Azasulfuryl Peptides: Synthesis and Biological Activity Journal of Medicinal Chemistry , vol. 59 , nº 10. p. 4740-4752. DOI: 10.1021/acs.jmedchem.6b00108.

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Résumé

Cyclic azasulfuryl (As) peptide analogs of the urotensin II (UII, 1, H-Glu-Thr-Pro-Asp-c[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH) fragment 4-11 were synthesized to explore the influences of backbone structure on biological activity. N-Aminosulfamides were inserted as surrogates of the Trp7 and Lys8 residues in the biologically relevant Trp-Lys-Tyr triad. A combination of solution- and solid-phase methods were used to prepare novel UII(4-11) analogs 6-11 by routes featuring alkylation of azasulfuryl-glycine tripeptide precursors to install various side chains. The pharmacological profiles of derivatives 6-11 were tested in vitro using a competitive binding assay and ex vivo using a rat aortic ring bioassay. Although the analogs exhibited weak affinity for the urotensin II receptor (UT) without agonistic activity, azasulfuryl-UII(4-11) derivatives 7-9 reduced up to 50% of the effects of UII and urotensin II-related peptide (URP) without affecting their potency. © 2016 American Chemical Society.

Type de document:
Mots-clés libres: II RECEPTOR ANTAGONIST; PHARMACOPHORE MODEL; AMINO-ACID; EX-VIVO; ATHEROSCLEROSIS; INHIBITION; ACTIVATION; MODULATORS; ANALOGS; DESIGN
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 16 mai 2017 20:32
Dernière modification: 16 mai 2017 20:32
URI: http://espace.inrs.ca/id/eprint/4615

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