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Research ArticleCARDIOVASCULAR

Pharmacology of the Urotensin-II Receptor Antagonist Palosuran (ACT-058362; 1-[2-(4-Benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea Sulfate Salt): First Demonstration of a Pathophysiological Role of the Urotensin System

Martine Clozel, Christoph Binkert, Magdalena Birker-Robaczewska, Céline Boukhadra, Shuang-Shuang Ding, Walter Fischli, Patrick Hess, Boris Mathys, Keith Morrison, Celia Müller, Claus Müller, Oliver Nayler, Changbin Qiu, Markus Rey, Michael W. Scherz, Jörg Velker, Thomas Weller, Jian-Fei Xi and Patrick Ziltener
Journal of Pharmacology and Experimental Therapeutics October 2004, 311 (1) 204-212; DOI: https://doi.org/10.1124/jpet.104.068320
Martine Clozel
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Magdalena Birker-Robaczewska
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Céline Boukhadra
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Shuang-Shuang Ding
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Walter Fischli
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Patrick Hess
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Boris Mathys
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Keith Morrison
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Celia Müller
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Claus Müller
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Abstract

Urotensin-II (U-II) is a cyclic peptide now described as the most potent vasoconstrictor known. U-II binds to a specific G protein-coupled receptor, formerly the orphan receptor GPR14, now renamed urotensin receptor (UT receptor), and present in mammalian species. Palosuran (ACT-058362; 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea sulfate salt) is a new potent and specific antagonist of the human UT receptor. ACT-058362 antagonizes the specific binding of 125I-labeled U-II on natural and recombinant cells carrying the human UT receptor with a high affinity in the low nanomolar range and a competitive mode of antagonism, revealed only with prolonged incubation times. ACT-058362 also inhibits U-II-induced calcium mobilization and mitogen-activated protein kinase phosphorylation. The binding inhibitory potency of ACT-058362 is more than 100-fold less on the rat than on the human UT receptor, which is reflected in a pD′2 value of 5.2 for inhibiting contraction of isolated rat aortic rings induced by U-II. In functional assays of short incubation times, ACT-058362 behaves as an apparent noncompetitive inhibitor. In vivo, intravenous ACT-058362 prevents the no-reflow phenomenon, which follows renal artery clamping in rats, without decreasing blood pressure and prevents the subsequent development of acute renal failure and the histological consequences of ischemia. In conclusion, the in vivo efficacy of the specific UT receptor antagonist ACT-058362 reveals a role of endogenous U-II in renal ischemia. As a selective renal vasodilator, ACT-058362 may be effective in other renal diseases.

Footnotes

  • doi:10.1124/jpet.104.068320.

  • ABBREVIATIONS: U-II, urotensin-II; UT, urotensin receptor; FBS, fetal bovine serum; CHO, Chinese hamster ovary; DMEM, Dulbecco's modified Eagle's medium; PBS, phosphate-buffered saline; FLIPR, fluorometric image plate reader; BSA, bovine serum albumin; DMSO, dimethyl sulfoxide; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; MAP, mean arterial blood pressure; HR, heart rate; GFR, glomerular filtration rate; ARF, acute renal failure; ACT-058362, palosuran.

    • Received March 15, 2004.
    • Accepted May 12, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 311 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 311, Issue 1
1 Oct 2004
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Pharmacology of the Urotensin-II Receptor Antagonist Palosuran (ACT-058362; 1-[2-(4-Benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea Sulfate Salt): First Demonstration of a Pathophysiological Role of the Urotensin System
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Research ArticleCARDIOVASCULAR

Pharmacology of the Urotensin-II Receptor Antagonist Palosuran (ACT-058362; 1-[2-(4-Benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea Sulfate Salt): First Demonstration of a Pathophysiological Role of the Urotensin System

Martine Clozel, Christoph Binkert, Magdalena Birker-Robaczewska, Céline Boukhadra, Shuang-Shuang Ding, Walter Fischli, Patrick Hess, Boris Mathys, Keith Morrison, Celia Müller, Claus Müller, Oliver Nayler, Changbin Qiu, Markus Rey, Michael W. Scherz, Jörg Velker, Thomas Weller, Jian-Fei Xi and Patrick Ziltener
Journal of Pharmacology and Experimental Therapeutics October 1, 2004, 311 (1) 204-212; DOI: https://doi.org/10.1124/jpet.104.068320

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Research ArticleCARDIOVASCULAR

Pharmacology of the Urotensin-II Receptor Antagonist Palosuran (ACT-058362; 1-[2-(4-Benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea Sulfate Salt): First Demonstration of a Pathophysiological Role of the Urotensin System

Martine Clozel, Christoph Binkert, Magdalena Birker-Robaczewska, Céline Boukhadra, Shuang-Shuang Ding, Walter Fischli, Patrick Hess, Boris Mathys, Keith Morrison, Celia Müller, Claus Müller, Oliver Nayler, Changbin Qiu, Markus Rey, Michael W. Scherz, Jörg Velker, Thomas Weller, Jian-Fei Xi and Patrick Ziltener
Journal of Pharmacology and Experimental Therapeutics October 1, 2004, 311 (1) 204-212; DOI: https://doi.org/10.1124/jpet.104.068320
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