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
| Autor: | Martine Clozel, Celine Boukhadra, Shuang-Shuang Ding, Michael Scherz, Keith Morrison, Oliver Nayler, Claus Müller, Christophe Binkert, Thomas Weller, Patrick Hess, Jian-Fei Xi, Celia Muller, Magdalena Birker-Robaczewska, Boris Mathys, Walter Fischli, Changbin Qiu, Patrick Ziltener, Markus Rey, Jörg Velker |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Male
medicine.medical_specialty Urotensins Aorta Thoracic Pharmacology Urotensin-II receptor Biology Receptors G-Protein-Coupled Ischemia Internal medicine medicine Animals Humans Urea Renal Insufficiency Rats Wistar Receptor Protein kinase A Orphan receptor Renal ischemia Antagonist Rats Disease Models Animal Endocrinology Vasoconstriction Competitive antagonist Quinolines Molecular Medicine Kidney Diseases Antagonism |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 311:204-212 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.104.068320 |
| Popis: | 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 (125)I-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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|