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Development and pharmacological characterization of conformationally constrained urotensin II-related peptide agonists.

Authors
  • Chatenet, David
  • Folch, Benjamin
  • Feytens, Debby
  • Létourneau, Myriam
  • Tourwé, Dirk
  • Doucet, Nicolas
  • Fournier, Alain
Type
Published Article
Journal
Journal of Medicinal Chemistry
Publisher
American Chemical Society
Publication Date
Dec 12, 2013
Volume
56
Issue
23
Pages
9612–9622
Identifiers
DOI: 10.1021/jm401153j
PMID: 24251366
Source
Medline
License
Unknown

Abstract

Urotensin II (UII) and its paralog peptide, urotensin II-related peptide (URP), exert not only common but also divergent actions through the activation of UT, a specific membrane-bound receptor that belongs to the 1A G protein-coupled receptor subclass. In this study, we have designed and synthesized new URP analogues in which the intracyclic Trp residue was replaced with natural, unnatural, and constrained amino acids to determine important physicochemical features for receptor binding and activation. The biological data, highlighting the potent agonistic behavior of [Tiq(4)]URP and [Tpi(4)]URP, also suggest that the Trp residue, and more specifically the indole ring, is not critical for receptor interaction and could in fact be involved in the intramolecular stabilization of the bioactive conformation of URP. Finally, these analogues, which are intracyclic constrained URP-based agonists, could represent useful pharmacological tools for the study of the urotensinergic system.

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