Palosuran inhibits binding to primate UT receptors in cell membranes but demonstrates differential activity in intact cells and vascular tissues

Br J Pharmacol. 2008 Oct;155(3):374-86. doi: 10.1038/bjp.2008.266. Epub 2008 Jun 30.


Background and purpose: The recent development of the UT ligand palosuran (1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea sulphate salt) has led to the proposition that urotensin-II (U-II) plays a significant pathological role in acute and chronic renal injury in the rat.

Experimental approach: In the present study, the pharmacological properties of palosuran were investigated further using a series of radioligand binding and functional bioassays.

Key results: Palosuran functioned as a 'primate-selective' UT ligand in recombinant cell membranes (monkey and human UT K(i) values of 4 +/- 1 and 5 +/- 1 nM), lacking appreciable affinity at other mammalian UT isoforms (rodent and feline K(i) values >1 microM). Paradoxically, however, palosuran lost significant (10- to 54-fold) affinity for native and recombinant human UT when radioligand binding was performed in intact cells (K(i) values of 50 +/- 3 and 276 +/- 67 nM). In accordance, palosuran also exhibited diminished activity in hUT (human urotensin-II receptor)-CHO (Chinese hamster ovary) cells (IC50 323 +/- 67 nM) and isolated arteries (K(b)>10 microM in rat aorta; K(b)>8.5 microM in cat arteries; K(b)>1.6 microM in monkey arteries; K(b) 2.2 +/- 0.6 microM in hUT transgenic mouse aorta). Relative to recombinant binding K(i) values, palosuran was subjected to a 392- to 690-fold reduction in functional activity in monkey isolated arteries. Such phenomena were peculiar to palosuran and were not apparent with an alternative chemotype, SB-657510 (2-bromo-N-[4-chloro-3-((R)-1-methyl-pyrrolidin-3-yloxy)-phenyl]-4,5-dimethoxybenzenesulphonamide HCl).

Conclusions and implications: Collectively, such findings suggest that caution should be taken when interpreting data generated using palosuran. The loss of UT affinity/activity observed in intact cells and tissues cf. membranes offers a potential explanation for the disappointing clinical efficacy reported with palosuran in diabetic nephropathy patients. As such, the (patho)physiological significance of U-II in diabetic renal dysfunction remains uncertain.

MeSH terms

  • Animals
  • CHO Cells
  • Cats
  • Cell Line
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cricetinae
  • Cricetulus
  • Humans
  • Inhibitory Concentration 50
  • Macaca fascicularis
  • Male
  • Mice
  • Quinolines / administration & dosage
  • Quinolines / pharmacology*
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Receptors, G-Protein-Coupled / drug effects*
  • Receptors, G-Protein-Coupled / metabolism
  • Species Specificity
  • Urea / administration & dosage
  • Urea / analogs & derivatives*
  • Urea / pharmacology
  • Urotensins / drug effects*
  • Urotensins / metabolism


  • Quinolines
  • Receptors, G-Protein-Coupled
  • UTS2R protein, human
  • Urotensins
  • Urea
  • urotensin II
  • 1-(2-(4-benzyl-4-hydroxypiperidin-1-yl)ethyl)-3-(2-methylquinolin-4-yl)urea