title: 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.
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 (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.
authors.affiliation: Actelion Pharmaceuticals Ltd., Innovation Centre, Gewerbestrasse 16, Allschwil, CH-4123, Switzerland. martine.clozel@actelion.com
authors.forename: Martine
authors.initials: M
authors.lastname: Clozel
authors.forename: Christoph
authors.initials: C
authors.lastname: Binkert
authors.forename: Magdalena
authors.initials: M
authors.lastname: Birker-Robaczewska
authors.forename: Céline
authors.initials: C
authors.lastname: Boukhadra
authors.forename: Shuang-Shuang
authors.initials: SS
authors.lastname: Ding
authors.forename: Walter
authors.initials: W
authors.lastname: Fischli
authors.forename: Patrick
authors.initials: P
authors.lastname: Hess
authors.forename: Boris
authors.initials: B
authors.lastname: Mathys
authors.forename: Keith
authors.initials: K
authors.lastname: Morrison
authors.forename: Celia
authors.initials: C
authors.lastname: Müller
authors.forename: Claus
authors.initials: C
authors.lastname: Müller
authors.forename: Oliver
authors.initials: O
authors.lastname: Nayler
authors.forename: Changbin
authors.initials: C
authors.lastname: Qiu
authors.forename: Markus
authors.initials: M
authors.lastname: Rey
authors.forename: Michael W
authors.initials: MW
authors.lastname: Scherz
authors.forename: Jörg
authors.initials: J
authors.lastname: Velker
authors.forename: Thomas
authors.initials: T
authors.lastname: Weller
authors.forename: Jian-Fei
authors.initials: JF
authors.lastname: Xi
authors.forename: Patrick
authors.initials: P
authors.lastname: Ziltener
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D006801:Humans; D007511:Ischemia / Q000150:complications; D007674:Kidney Diseases / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D051437:Renal Insufficiency / Q000503:physiopathology; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D014579:Urotensins / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D011804:Quinolines; D043562:Receptors, G-Protein-Coupled; D014579:Urotensins; C473142:Uts2r protein, rat; D014508:Urea; C493249:1-(2-(4-benzyl-4-hydroxypiperidin-1-yl)ethyl)-3-(2-methylquinolin-4-yl)urea