In vitro characterization of Ro 46‐2005, a novel synthetic non‐peptide endothelin antagonist of ET<sub>A</sub> and ET<sub>B</sub> receptors

Breu, Volker; Löffler, Bernd–Michael; Clozel, Martine

doi:10.1016/0014-5793(93)81713-a

Cited by 59 publications

(18 citation statements)

References 30 publications

(34 reference statements)

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“…Microsomal cell membranes were prepared according to Breu et al (1993). Membrane binding assays were performed in 200 l of PBS, pH 7.4, 1 mM EDTA, 0.5% (w/v) BSA fraction V, and 2.5% DMSO in polypropylene microtiter plates.…”

Section: I-urotensin II Binding Assaysmentioning

confidence: 99%

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

Clozel¹,

Binkert²,

Birker‐Robaczewska³

et al. 2004

The Journal of Pharmacology and Experimental Therapeutics

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116

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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 Ilabeled 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 pDЈ 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.

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Section: I-urotensin II Binding Assaysmentioning

confidence: 99%

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

Clozel¹,

Binkert²,

Birker‐Robaczewska³

et al. 2004

The Journal of Pharmacology and Experimental Therapeutics

Self Cite

116

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“…13 [147-15 11). Combined ETA/ETB-receptor antagonists also are now available [148]. These tools allow exact determination of the role of endogenously formed endothelin in various forms of cardiovascular disease.…”

Section: Endothelin Antagonistsmentioning

confidence: 99%

The endothelium as a target and mediator of cardiovascular disease

1993

Eur J Clin Investigation

105

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“…Ro 46-8443, a sulfonamide with central pyrimidine moiety, is structurally related to the recently described antagonists Ro 46-2005 [22,30] and bosentan [21], which bind to both ETA and ETB receptors with comparable potency. However, replacement of the second pyrimidine, found in the bosentan structure, by a p-methoxy-phenyl moiety and replacement of the hydroxy-ethoxy side chain by a glycerol residue resulted in an ETB receptor selective antagonist.…”

Section: Discussionmentioning

confidence: 99%

“…Microsomal membranes were prepared as described earlier [22] from human placenta, porcine trachea, rat trachea, baculovirus infected insect cells expressing recombinant human ETA receptor and CHO cells expressing recombinant ETB receptor cloned from human placenta [23,24], and stored in aliquots at -80°C. Protein was determined according to the method of Lowry [25].…”

Section: Preparation Oj Membranesmentioning

confidence: 99%

In vitro characterisation of Ro 46‐8443, the first non‐peptide antagonist selective for the endothelin ET_B receptor

Breu¹,

Clozel²,

Burri³

et al. 1996

FEBS Letters

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In vitro characterization of Ro 46‐2005, a novel synthetic non‐peptide endothelin antagonist of ET_A and ET_B receptors

Cited by 59 publications

References 30 publications

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

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

The endothelium as a target and mediator of cardiovascular disease

In vitro characterisation of Ro 46‐8443, the first non‐peptide antagonist selective for the endothelin ET_B receptor

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In vitro characterization of Ro 46‐2005, a novel synthetic non‐peptide endothelin antagonist of ETA and ETB receptors

Cited by 59 publications

References 30 publications

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

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

The endothelium as a target and mediator of cardiovascular disease

In vitro characterisation of Ro 46‐8443, the first non‐peptide antagonist selective for the endothelin ETB receptor

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In vitro characterization of Ro 46‐2005, a novel synthetic non‐peptide endothelin antagonist of ET_A and ET_B receptors

In vitro characterisation of Ro 46‐8443, the first non‐peptide antagonist selective for the endothelin ET_B receptor