title: Structure-activity relationships of human urotensin II and related analogues on rat aortic ring contraction.
abstract: The sequence of human urotensin II (UII) has been recently established as H-Glu-Thr-Pro-Asp-Cys-Phe-Trp-Lys-Tyr-Cys-Val-OH, and it has been reported that UII is the most potent mammalian vasoconstrictor peptide identified so far. A series of UII analogues was synthesized, and the contractile activity of each compound was studied in vitro using de-endothelialised rat aortic rings. Replacement of each amino acid by an L-alanine or by a D-isomer showed that the N- and C-terminal residues flanking the cyclic region of the amidated peptide were relatively tolerant to substitution. Conversely, replacement of any residue of the cyclic region significantly reduced the contractile activity of the molecule. The octapeptide UII(4-11) was 4 times more potent than UII, indicating that the C-terminal region of the molecule possesses full biological activity. Alanine or D-isomer substitutions in UII(4-11) or in UII(4-11)-NH2, respectively, showed a good correlation with the results obtained for UII-NH2. Disulfide bridge disruption or replacement of the cysteine residues by their D-enantiomers markedly reduced the vasoconstrictor effect of UII and its analogues. In contrast, acetylation of the N-terminal residue of UII and UII-NH2 enhanced the potency of the peptide. Finally, monoiodination of the Tyr6 residue in UII(4-11) increased by 5 fold the potency of the peptide in the aortic ring bioassay. This structure-activity relationship study should provide useful information for the rational design of selective and potent UII receptor agonists and antagonists.
authors.affiliation: Centre de Biochimie Structurale, CNRS UMR 5048, INSERM UMR 554, Université de Montpellier 1, 34090 Montpellier, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Labarrère
authors.forename: David
authors.initials: D
authors.lastname: Chatenet
authors.forename: Jérôme
authors.initials: J
authors.lastname: Leprince
authors.forename: Céline
authors.initials: C
authors.lastname: Marionneau
authors.forename: Gervaise
authors.initials: G
authors.lastname: Loirand
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Tonon
authors.forename: Christophe
authors.initials: C
authors.lastname: Dubessy
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Scalbert
authors.forename: Bruno
authors.initials: B
authors.lastname: Pfeiffer
authors.forename: Pierre
authors.initials: P
authors.lastname: Renard
authors.forename: Bernard
authors.initials: B
authors.lastname: Calas
authors.forename: Pierre
authors.initials: P
authors.lastname: Pacaud
authors.forename: Hubert
authors.initials: H
authors.lastname: Vaudry
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014579:Urotensins / Q000737:chemistry / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000737:chemistry / Q000494:pharmacology
chemical_list: D010446:Peptide Fragments; D014579:Urotensins; D014662:Vasoconstrictor Agents; C029677:urotensin II