Structure–Activity Relationships of Human Urotensin II and Related Analogues on Rat Aortic Ring Contraction
| Autor: | Gervaise Loirand, Pierre Renard, Pierre Pacaud, Jérôme Leprince, David Chatenet, Hubert Vaudry, Marie-Christine Tonon, Christophe Dubessy, Elizabeth Scalbert, Bernard Calas, Céline Marionneau, Bruno Pfeiffer, Patricia Labarrère |
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| Přispěvatelé: | Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Fédératif de Recherches Multidisciplinaires sur les Peptides (IFRMP 23), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, Les Laboratoires SERVIER, Institut de Recherche Servier |
| Rok vydání: | 2003 |
| Předmět: |
Male
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology Aorta Thoracic Peptide MESH: Amino Acid Sequence [CHIM.THER]Chemical Sciences/Medicinal Chemistry MESH: Dose-Response Relationship Drug chemistry.chemical_compound MESH: Structure-Activity Relationship 0302 clinical medicine [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB] Drug Discovery Vasoconstrictor Agents MESH: Animals MESH: Peptide Fragments Receptor chemistry.chemical_classification Alanine 0303 health sciences Biological activity General Medicine Amino acid Biochemistry MESH: Rats Stereochemistry Urotensins MESH: Aorta Thoracic Molecular Sequence Data In Vitro Techniques Structure-Activity Relationship MESH: Vasoconstrictor Agents 03 medical and health sciences Animals Humans Amino Acid Sequence Rats Wistar 030304 developmental biology MESH: In Vitro Techniques Pharmacology MESH: Humans MESH: Molecular Sequence Data MESH: Urotensins Dose-Response Relationship Drug MESH: Rats Wistar Peptide Fragments MESH: Male In vitro Rats chemistry [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology Urotensin-II 030217 neurology & neurosurgery Cysteine |
| Zdroj: | Journal of Enzyme Inhibition and Medicinal Chemistry Journal of Enzyme Inhibition and Medicinal Chemistry, Informa Healthcare, 2003, 18 (2), pp.77-88. ⟨10.1080/1475636031000093507⟩ |
| ISSN: | 1475-6374 1475-6366 |
| DOI: | 10.1080/1475636031000093507 |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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