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.