Article date: October 2008
By: D J Behm, J J McAtee, J W Dodson, M J Neeb, H E Fries, C A Evans, R R Hernandez, K D Hoffman, S M Harrison, J M Lai, C Wu, N V Aiyar, E H Ohlstein, S A Douglas in Volume 155, Issue 3, pages 374-386
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 Ki values of 4±1 and 5±1 nM), lacking appreciable affinity at other mammalian UT isoforms (rodent and feline Ki values >1 μM). Paradoxically, however, palosuran lost significant (10‐ to 54‐fold) affinity for native and recombinant human UT when radioligand binding was performed in intact cells (Ki 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 (Kb>10 μM in rat aorta; Kb>8.5 μM in cat arteries; Kb>1.6 μM in monkey arteries; Kb 2.2±0.6 μM in hUT transgenic mouse aorta). Relative to recombinant binding Ki 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.
DOI: 10.1038/bjp.2008.266
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