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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on June 13, 2003; DOI: 10.1124/jpet.103.052415

0022-3565/03/3063-1200-1209$20.00
JPET 306:1200-1209, 2003
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CARDIOVASCULAR

Functional and Binding Characterizations of Urotensin II-Related Peptides in Human and Rat Urotensin II-Receptor Assay

Alexandre Brkovic, Almut Hattenberger, Evi Kostenis1, Thomas Klabunde, Stefanie Flohr2, Michael Kurz, Steve Bourgault, and Alain Fournier

Institut national de la recherche scientifique (A.B., S.B., A.F.), Université du Québec, INRS-Institut Armand-Frappier, Pointe-Claire, Montréal, Quebec, Canada; and Disease Group Cardiovascular (A.H., E.K.), Lead Generation Chemistry (T.K., S.F., M.K.), Aventis Pharma Germany GmbH, Industriepark Hoechst, Frankfurt am Main, Germany.

Urotensin II (U-II; cyclo5-10[H-Glu-Thr-Pro-Asp-Cys-Phe-Trp-Lys-Tyr-Cys-Val-OH]) is a potent vasoconstrictor in mammals, and it is postulated that it plays a central role in cardiovascular homeostasis. Thus, we initiated a structure-to-function analysis of this peptide characterized by a N-terminal tail and a cyclic core formed through a disulfide bridging. A total of 41 analogs focusing on these characteristics were developed and evaluated using a binding assay on membranes from a stable HEK-293 cell line containing the human or rat U-II receptor, a functional assay for Ca2+ mobilization on transiently transfected CHO-K1 cells with the human or rat U-II receptor, and a rat thoracic aorta bioassay. At first, the focus was applied on peptide compounds containing exocyclic modifications. From this series, it appeared that only valine-11 played a significant role although it is not an essential amino acid. Similarly, endocyclic and ring transformations of hU-II were also studied. In most cases, a detrimental effect on affinity and biological activity was observed. However, two compounds, [Tyr6]hU-II and [Phe9]hU-II, retained affinity and activity. So far, our binding, functional, and pharmacological data clearly demonstrated the minor contribution of the N-terminal segment and the essential role of the cyclic structure. More particularly, three residues within the loop, i.e., Trp-7, Lys-8, and Tyr-9, are required for receptor recognition and activation. This three-pole feature, kept by the disulfide bond in a correct spatial arrangement, appears as the key pharmacophore for the U-II receptor.

Received April 1, 2003; accepted May 28, 2003.

Address correspondence to: Dr. Alain Fournier, Laboratoire d'études moléculaires et pharmacologiques des peptides, Institut national de la recherche scientifique, Université du Québec, INRS, Institut Armand-Frappier, 245 boul. Hymus, Pointe-Claire (Montréal), QC, H9R 1G6, Canada. E-mail: alain.fournier{at}inrs-iaf.uquebec.ca






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