| Autor: |
Stephen A. Douglas, Charlene Wu, K D Hoffman, Michael J. Neeb, R R Hernandez, Stephen M. Harrison, Eliot H. Ohlstein, Jason W. Dodson, John J. McAtee, Nambi Aiyar, Harvey E. Fries, David J. Behm, J M Lai, Christopher A. Evans |
| Rok vydání: |
2008 |
| Předmět: |
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| Zdroj: |
British Journal of Pharmacology. 155:374-386 |
| ISSN: |
0007-1188 |
| Popis: |
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. British Journal of Pharmacology (2008) 155, 374–386; doi:10.1038/bjp.2008.266; published online 30 June 2008 |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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