Identification of novel Urotensin-II receptor antagonists with potent inhibition of U-II induced pressor response in mice.

European journal of pharmacology 2020 Nov 05

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Urotensin II (U-II) has been found to be one of the most potent vasoconstrictor (Ames et al., 1999; Bohm et al., 2002) reported till date. U-II exerts its response via activation of a G-protein coupled receptor, Urotensin II receptor(UT). Binding of U-II to UT leads to an instant increase in the inositol phosphate turnover and intracellular Ca2+. Such an instant Ca2+ release and potent vasoconstriction exerted by U-II is expected to have an important role in the progression of cardiac diseases. We have previously shown that UT antagonist DS37001789 prevents U-II induced blood pressure elevation in mice (Nishi et al., 2019) in a dose dependent manner, with potent efficacy at 30 and 100 mg/kg. Further to this, we have also shown that DS37001789 ameliorates mortality in pressure-overload mice with heart failure (Nishi et al., 2020). We therefore conducted an extensive structure-activity relationship studies to identify molecules with superior efficacy. In the present manuscript, we report the identification of two potent, non-peptide small molecule antagonists of Urotensin II receptor (UT), RCI-0879 and RCI-0298 which blocked the action of U-II, both in vitro and in vivo. These molecules were found to be very potent in in vitro Ca2+ and radioligand binding assays using human and mouse UT over-expressing CHO cells. RCI-0879 and RCI-0298 also exhibited superior efficacy in in vivo mouse pressor response model using C57BL/6 mice, compared to our initial molecules (Nishi et al., 2019) and demonstrated ED50 values of 3.2 mg/kg and 6.8 mg/kg respectively. Our findings reported herewith, further strengthen our concept and belief in UT antagonization as a potential therapeutic approach for the management of chronic heart failure. Copyright © 2020 Elsevier B.V. All rights reserved.

Citation

Ruchi Tandon, Ajay Soni, Rakesh K Singh, Reena Sodhi, Mahesh K Seth, Sandeep Sinha, Sudhir Sahdev, Ganesh Dhage, Biswajit Das, Sunanda G Dastidar, Raj Kumar Shriumalla, Kiyoaki Yonesu, Shinji Marumoto, Takahiro Nagayama. Identification of novel Urotensin-II receptor antagonists with potent inhibition of U-II induced pressor response in mice. European journal of pharmacology. 2020 Nov 05;886:173391