Nonpeptidic urotensin‐II receptor antagonists I: in vitro pharmacological characterization of SB‐706375

Medientyp: E-Artikel
Titel: Nonpeptidic urotensin‐II receptor antagonists I: in vitro pharmacological characterization of SB‐706375
Beteiligte: Douglas, Stephen A; Behm, David J; Aiyar, Nambi V; Naselsky, Diane; Disa, Jyoti; Brooks, David P; Ohlstein, Eliot H; Gleason, John G; Sarau, Henry M; Foley, James J; Buckley, Peter T; Schmidt, Dulcie B; Wixted, William E; Widdowson, Katherine; Riley, Graham; Jin, Jian; Gallagher, Timothy F; Schmidt, Stanley J; Ridgers, Lance; Christmann, Lisa T; Keenan, Richard M; Knight, Steven D; Dhanak, Dashyant
Erschienen: Wiley, 2005
Erschienen in: British Journal of Pharmacology, 145 (2005) 5, Seite 620-635
Sprache: Englisch
DOI: 10.1038/sj.bjp.0706229
ISSN: 0007-1188; 1476-5381
Schlagwörter: Pharmacology
Entstehung:
Anmerkungen:
Beschreibung: <jats:p> <jats:list list-type="explicit-label"> <jats:list-item><jats:p>SB‐706375 potently inhibited [<jats:sup>125</jats:sup>I]hU‐II binding to both mammalian recombinant and ‘native’ UT receptors (<jats:italic>K</jats:italic><jats:sub>i</jats:sub> 4.7±1.5 to 20.7±3.6 n<jats:sc>M</jats:sc> at rodent, feline and primate recombinant UT receptors and <jats:italic>K</jats:italic><jats:sub>i</jats:sub> 5.4±0.4 n<jats:sc>M</jats:sc> at the endogenous UT receptor in SJRH30 cells).</jats:p></jats:list-item> <jats:list-item><jats:p>Prior exposure to SB‐706375 (1 <jats:italic>μ</jats:italic><jats:sc>M</jats:sc>, 30 min) did not alter [<jats:sup>125</jats:sup>I]hU‐II binding affinity or density in recombinant cells (<jats:italic>K</jats:italic><jats:sub>D</jats:sub> 3.1±0.4 vs 5.8±0.9 n<jats:sc>M</jats:sc> and <jats:italic>B</jats:italic><jats:sub>max</jats:sub> 3.1±1.0 vs 2.8±0.8 pmol mg<jats:sup>−1</jats:sup>) consistent with a reversible mode of action.</jats:p></jats:list-item> <jats:list-item><jats:p>The novel, nonpeptidic radioligand [<jats:sup>3</jats:sup>H]SB‐657510, a close analogue of SB‐706375, bound to the monkey UT receptor (<jats:italic>K</jats:italic><jats:sub>D</jats:sub> 2.6±0.4 n<jats:sc>M</jats:sc>, <jats:italic>B</jats:italic><jats:sub>max</jats:sub> 0.86±0.12 pmol mg<jats:sup>−1</jats:sup>) in a manner that was inhibited by both U‐II isopeptides and SB‐706375 (<jats:italic>K</jats:italic><jats:sub>i</jats:sub> 4.6±1.4 to 17.6±5.4 n<jats:sc>M</jats:sc>) consistent with the sulphonamides and native U‐II ligands sharing a common UT receptor binding domain.</jats:p></jats:list-item> <jats:list-item><jats:p>SB‐706375 was a potent, competitive hU‐II antagonist across species with p<jats:italic>K</jats:italic><jats:sub>b</jats:sub> 7.29–8.00 in HEK293‐UT receptor cells (inhibition of [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub>‐mobilization) and p<jats:italic>K</jats:italic><jats:sub>b</jats:sub> 7.47 in rat isolated aorta (inhibition of contraction). SB‐706375 also reversed tone established in the rat aorta by prior exposure to hU‐II (<jats:italic>K</jats:italic><jats:sub>app</jats:sub>∼20 n<jats:sc>M</jats:sc>).</jats:p></jats:list-item> <jats:list-item><jats:p>SB‐706375 was a selective U‐II antagonist with 100‐fold selectivity for the human UT receptor compared to 86 distinct receptors, ion channels, enzymes, transporters and nuclear hormones (<jats:italic>K</jats:italic><jats:sub>i</jats:sub>/IC<jats:sub>50</jats:sub>>1 <jats:italic>μ</jats:italic><jats:sc>M</jats:sc>). Accordingly, the contractile responses induced in isolated aortae by KCl, phenylephrine, angiotensin II and endothelin‐1 were unaltered by SB‐706375 (1 <jats:italic>μ</jats:italic><jats:sc>M</jats:sc>).</jats:p></jats:list-item> <jats:list-item><jats:p>In summary, SB‐706375 is a high‐affinity, surmountable, reversible and selective nonpeptide UT receptor antagonist with cross‐species activity that will assist in delineating the pathophysiological actions of U‐II in mammals.</jats:p></jats:list-item> </jats:list> </jats:p><jats:p><jats:italic>British Journal of Pharmacology</jats:italic> (2005) <jats:bold>145</jats:bold>, 620–635. doi:<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.1038/sj.bjp.0706229">10.1038/sj.bjp.0706229</jats:ext-link></jats:p>
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