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

Br J Pharmacol. 2005 Jul;145(5):620-35. doi: 10.1038/sj.bjp.0706229.


1. SB-706375 potently inhibited [(125)I]hU-II binding to both mammalian recombinant and 'native' UT receptors (K(i) 4.7+/-1.5 to 20.7+/-3.6 nM at rodent, feline and primate recombinant UT receptors and K(i) 5.4+/-0.4 nM at the endogenous UT receptor in SJRH30 cells). 2. Prior exposure to SB-706375 (1 microM, 30 min) did not alter [(125)I]hU-II binding affinity or density in recombinant cells (K(D) 3.1+/-0.4 vs 5.8+/-0.9 nM and B(max) 3.1+/-1.0 vs 2.8+/-0.8 pmol mg(-1)) consistent with a reversible mode of action. 3. The novel, nonpeptidic radioligand [(3)H]SB-657510, a close analogue of SB-706375, bound to the monkey UT receptor (K(D) 2.6+/-0.4 nM, B(max) 0.86+/-0.12 pmol mg(-1)) in a manner that was inhibited by both U-II isopeptides and SB-706375 (K(i) 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. 4. SB-706375 was a potent, competitive hU-II antagonist across species with pK(b) 7.29-8.00 in HEK293-UT receptor cells (inhibition of [Ca(2+)](i)-mobilization) and pK(b) 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 (K(app) approximately 20 nM). 5. 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 (K(i)/IC(50)>1 microM). Accordingly, the contractile responses induced in isolated aortae by KCl, phenylephrine, angiotensin II and endothelin-1 were unaltered by SB-706375 (1 microM). 6. 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.

MeSH terms

  • Algorithms
  • Animals
  • Aorta, Thoracic / drug effects
  • Binding, Competitive / drug effects
  • Cats
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Haplorhini
  • Humans
  • In Vitro Techniques
  • Mice
  • Muscle Contraction / drug effects
  • Muscle, Smooth, Vascular / drug effects
  • Pyrrolidines / pharmacology*
  • Radioligand Assay
  • Rats
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / genetics*
  • Recombinant Proteins / metabolism
  • Rhabdomyosarcoma / metabolism
  • Species Specificity
  • Sulfonamides / pharmacology*


  • Pyrrolidines
  • Receptors, G-Protein-Coupled
  • Recombinant Proteins
  • SB-706375
  • Sulfonamides
  • UTS2R protein, human