التفاصيل البيبلوغرافية
| العنوان: |
Nonpeptidic urotensin-II receptor antagonists I: in vitro pharmacological characterization of SB-706375. |
| المؤلفون: |
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. |
| المصدر: |
British Journal of Pharmacology; Jul2005, Vol. 145 Issue 5, p620-635, 16p |
| مصطلحات موضوعية: |
MEMBRANE proteins, BLOOD circulation, ARTERIES, PATHOLOGICAL physiology, PHYSIOLOGY, MEDICAL sciences |
| مستخلص: |
SB-706375 potently inhibited [125I]hU-II binding to both mammalian recombinant and ‘native’ UT receptors (Ki 4.7±1.5 to 20.7±3.6 nM at rodent, feline and primate recombinant UT receptors and Ki 5.4±0.4 nM at the endogenous UT receptor in SJRH30 cells).Prior exposure to SB-706375 (1 μM, 30 min) did not alter [125I]hU-II binding affinity or density in recombinant cells (KD 3.1±0.4 vs 5.8±0.9 nM and Bmax 3.1±1.0 vs 2.8±0.8 pmol mg−1) consistent with a reversible mode of action.The novel, nonpeptidic radioligand [3H]SB-657510, a close analogue of SB-706375, bound to the monkey UT receptor (KD 2.6±0.4 nM, Bmax 0.86±0.12 pmol mg−1) in a manner that was inhibited by both U-II isopeptides and SB-706375 (Ki 4.6±1.4 to 17.6±5.4 nM) consistent with the sulphonamides and native U-II ligands sharing a common UT receptor binding domain.SB-706375 was a potent, competitive hU-II antagonist across species with pKb 7.29–8.00 in HEK293-UT receptor cells (inhibition of [Ca2+]i-mobilization) and pKb 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 (Kapp∼20 nM).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 (Ki/IC50>1 μM). Accordingly, the contractile responses induced in isolated aortae by KCl, phenylephrine, angiotensin II and endothelin-1 were unaltered by SB-706375 (1 μM).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.British Journal of Pharmacology (2005) 145, 620–635. doi:10.1038/sj.bjp.0706229 Published online 25 April 2005 [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
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