ArticleBritish journal of pharmacology2015
The orally active urotensin receptor antagonist, KR36676, attenuates cellular and cardiac hypertrophy.
Article in British journal of pharmacology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 26 citations in OpenAlex.
- Inhibition of U-II/UT signaling ameliorates cystitis-associated bladder hyperactivity by targeting the RhoA/Rho-kinase pathway.The Kaohsiung journal of medical sciences · 2022Article
- Classification models and SAR analysis on CysLT1 receptor antagonists using machine learning algorithms.Molecular diversity · 2021Article
- Insights into the Molecular Determinants Involved in Urocontrin and Urocontrin A Action.ACS medicinal chemistry letters · 2020Article
- The urotensin II receptor antagonist DS37001789 ameliorates mortality in pressure-overload mice with heart failure.Heliyon · 2020Article
- A novel role of G protein-coupled receptor kinase 5 in urotensin II-stimulated cellular hypertrophy in H9c2Molecular and cellular biochemistry · 2016Article
- Blockade of Urotensin II Receptor Prevents Vascular Dysfunction.Biomolecules & therapeutics · 2016Article
- Cardioprotective Effect ofFrontiers in pharmacology · 2016Article
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeBlockade of the actions of urotensin-II (U-II) mediated by the urotensin (UT) receptor should improve cardiac function and prevent cardiac remodelling in cardiovascular disease. Here, we have evaluated the pharmacological properties of the recently identified UT receptor antagonist, 2-(6,7-dichloro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)-N-methyl-N-(2-(pyrrolidin-1-yl)-1-(4-(thiophen-3-yl)phenyl) ethyl)acetamide (KR36676). EXPERIMENTAL APPROACH: Pharmacological properties of KR36676 were studied in a range of in vitro assays (receptor binding, calcium mobilization, stress fibre formation, cellular hypertrophy) and in vivo animal models such as cardiac hypertrophy induced by transverse aortic constriction (TAC) or myocardial infarction (MI). KEY
resultsKR36676 displayed high binding affinity for the UT receptor (Ki : 0.7 nM), similar to that of U-II (0.4 nM), and was a potent antagonist at that receptor (IC50 : 4.0 nM). U-II-induced stress fibre formation and cellular hypertrophy were significantly inhibited with low concentrations of KR36676 (≥0.01 μM). Oral administration of KR36676 (30 mg·kg(-1) ) in a TAC model in mice attenuated cardiac hypertrophy and myocardial fibrosis. Moreover, KR36676 restored cardiac function and myocyte size in rats with MI-induced cardiac hypertrophy. CONCLUSIONS AND IMPLICATIONS: A highly potent UT receptor antagonist exerted anti-hypertrophic effects not only in infarcted rat hearts but also in pressure-overloaded mouse hearts. KR36676 could be a valuable pharmacological tool in elucidating the complicated physiological role of U-II and UT receptors in cardiac hypertrophy.
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