Palosuran inhibits binding to primate UT receptors in cell membranes but demonstrates differential activity in intact cells and vascular tissues
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 th...
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| Veröffentlicht in: | British journal of pharmacology 2008-10, Vol.155 (3), p.374-386 |
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| creator | Behm, D J McAtee, J J Dodson, J W Neeb, M J Fries, H E Evans, C A Hernandez, R R Hoffman, K D Harrison, S M Lai, J M Wu, C Aiyar, N V Ohlstein, E H Douglas, S A |
| description | 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 |
| doi_str_mv | 10.1038/bjp.2008.266 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2567886</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1563267121</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4815-5b7c800e4ac2ee69f7c6a9763a2999c924707e23f97f47ba01405b75277b2bb43</originalsourceid><addsrcrecordid>eNp9kU9v1DAQxS0EokvhxhlZSNzI1n8S27kglarQSpXaQ3u2bMdpvUqcxXYW7bfgI3e2uyr0wsmy5vdm3sxD6CMlS0q4OrGr9ZIRopZMiFdoQWspqoYr-hotCCGyolSpI_Qu5xUhUJTNW3REVaNkzfgC_bkxw5TnZCIO8SHYUDK2IXYh3uMy4XUKoyke393i5J1flyllALHzw4BHP1oQelDMBXd-nGIuCfCMu9D3PvlYghmwcSVsQtnuhCEW-D7pMzaxwxuT3TyYhEvIefb5PXrTmyH7D4f3GN39OL89u6iurn9enp1eVa5WtKkaK50ixNfGMe9F20snTCsFN6xtW9eyWhLpGe9b2dfSGlidgKZhUlpmbc2P0bd93_VsR9858JrMoJ8WTls9maBfVmJ40PfTRrNGSKUENPh8aJCmX2C86NU0pwieNaOSEUEaDtDXPeTSlHPy_fMASvQuPg3x6V18GuID_NO_pv7Ch7wA-HIA4Gxm6OH8LuRnjhHIl9QSOLrnfofBb_87VH-_ueBUNPwRHsS2Dw</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>217206053</pqid></control><display><type>article</type><title>Palosuran inhibits binding to primate UT receptors in cell membranes but demonstrates differential activity in intact cells and vascular tissues</title><source>Wiley Free Content</source><source>MEDLINE</source><source>Wiley Online Library Journals Frontfile Complete</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><creator>Behm, D J ; McAtee, J J ; Dodson, J W ; Neeb, M J ; Fries, H E ; Evans, C A ; Hernandez, R R ; Hoffman, K D ; Harrison, S M ; Lai, J M ; Wu, C ; Aiyar, N V ; Ohlstein, E H ; Douglas, S A</creator><creatorcontrib>Behm, D J ; McAtee, J J ; Dodson, J W ; Neeb, M J ; Fries, H E ; Evans, C A ; Hernandez, R R ; Hoffman, K D ; Harrison, S M ; Lai, J M ; Wu, C ; Aiyar, N V ; Ohlstein, E H ; Douglas, S A</creatorcontrib><description>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</description><identifier>ISSN: 0007-1188</identifier><identifier>EISSN: 1476-5381</identifier><identifier>DOI: 10.1038/bjp.2008.266</identifier><identifier>PMID: 18587423</identifier><identifier>CODEN: BJPCBM</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>ACT‐058362 ; Animals ; antagonist ; Associated diseases and complications ; Biological and medical sciences ; Cats ; Cell Line ; Cell Membrane - drug effects ; Cell Membrane - metabolism ; CHO Cells ; Cricetinae ; Cricetulus ; Diabetes. Impaired glucose tolerance ; diabetic nephropathy ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Etiopathogenesis. Screening. Investigations. Target tissue resistance ; GPR14 ; G‐protein‐coupled receptor ; Humans ; Inhibitory Concentration 50 ; Kidneys ; Macaca fascicularis ; Male ; Medical sciences ; Mice ; Nephrology. Urinary tract diseases ; palosuran ; Pharmacology. Drug treatments ; Quinolines - administration & dosage ; Quinolines - pharmacology ; Radioligand Assay ; Rats ; Rats, Sprague-Dawley ; Rats, Wistar ; Receptors, G-Protein-Coupled - drug effects ; Receptors, G-Protein-Coupled - metabolism ; Research Papers ; SB‐657510 ; Species Specificity ; Urea - administration & dosage ; Urea - analogs & derivatives ; Urea - pharmacology ; Urinary system involvement in other diseases. Miscellaneous ; Urotensins - drug effects ; Urotensins - metabolism ; urotensin‐II</subject><ispartof>British journal of pharmacology, 2008-10, Vol.155 (3), p.374-386</ispartof><rights>2008 British Pharmacological Society</rights><rights>2008 INIST-CNRS</rights><rights>Copyright Nature Publishing Group Oct 2008</rights><rights>Copyright 2008, Macmillan Publishers Limited 2008 Macmillan Publishers Limited</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4815-5b7c800e4ac2ee69f7c6a9763a2999c924707e23f97f47ba01405b75277b2bb43</citedby><cites>FETCH-LOGICAL-c4815-5b7c800e4ac2ee69f7c6a9763a2999c924707e23f97f47ba01405b75277b2bb43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2567886/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2567886/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,1411,1427,27901,27902,45550,45551,46384,46808,53766,53768</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20775047$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18587423$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Behm, D J</creatorcontrib><creatorcontrib>McAtee, J J</creatorcontrib><creatorcontrib>Dodson, J W</creatorcontrib><creatorcontrib>Neeb, M J</creatorcontrib><creatorcontrib>Fries, H E</creatorcontrib><creatorcontrib>Evans, C A</creatorcontrib><creatorcontrib>Hernandez, R R</creatorcontrib><creatorcontrib>Hoffman, K D</creatorcontrib><creatorcontrib>Harrison, S M</creatorcontrib><creatorcontrib>Lai, J M</creatorcontrib><creatorcontrib>Wu, C</creatorcontrib><creatorcontrib>Aiyar, N V</creatorcontrib><creatorcontrib>Ohlstein, E H</creatorcontrib><creatorcontrib>Douglas, S A</creatorcontrib><title>Palosuran inhibits binding to primate UT receptors in cell membranes but demonstrates differential activity in intact cells and vascular tissues</title><title>British journal of pharmacology</title><addtitle>Br J Pharmacol</addtitle><description>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</description><subject>ACT‐058362</subject><subject>Animals</subject><subject>antagonist</subject><subject>Associated diseases and complications</subject><subject>Biological and medical sciences</subject><subject>Cats</subject><subject>Cell Line</subject><subject>Cell Membrane - drug effects</subject><subject>Cell Membrane - metabolism</subject><subject>CHO Cells</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Diabetes. Impaired glucose tolerance</subject><subject>diabetic nephropathy</subject><subject>Endocrine pancreas. Apud cells (diseases)</subject><subject>Endocrinopathies</subject><subject>Etiopathogenesis. Screening. Investigations. Target tissue resistance</subject><subject>GPR14</subject><subject>G‐protein‐coupled receptor</subject><subject>Humans</subject><subject>Inhibitory Concentration 50</subject><subject>Kidneys</subject><subject>Macaca fascicularis</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Nephrology. Urinary tract diseases</subject><subject>palosuran</subject><subject>Pharmacology. Drug treatments</subject><subject>Quinolines - administration & dosage</subject><subject>Quinolines - pharmacology</subject><subject>Radioligand Assay</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Rats, Wistar</subject><subject>Receptors, G-Protein-Coupled - drug effects</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>Research Papers</subject><subject>SB‐657510</subject><subject>Species Specificity</subject><subject>Urea - administration & dosage</subject><subject>Urea - analogs & derivatives</subject><subject>Urea - pharmacology</subject><subject>Urinary system involvement in other diseases. Miscellaneous</subject><subject>Urotensins - drug effects</subject><subject>Urotensins - metabolism</subject><subject>urotensin‐II</subject><issn>0007-1188</issn><issn>1476-5381</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9kU9v1DAQxS0EokvhxhlZSNzI1n8S27kglarQSpXaQ3u2bMdpvUqcxXYW7bfgI3e2uyr0wsmy5vdm3sxD6CMlS0q4OrGr9ZIRopZMiFdoQWspqoYr-hotCCGyolSpI_Qu5xUhUJTNW3REVaNkzfgC_bkxw5TnZCIO8SHYUDK2IXYh3uMy4XUKoyke393i5J1flyllALHzw4BHP1oQelDMBXd-nGIuCfCMu9D3PvlYghmwcSVsQtnuhCEW-D7pMzaxwxuT3TyYhEvIefb5PXrTmyH7D4f3GN39OL89u6iurn9enp1eVa5WtKkaK50ixNfGMe9F20snTCsFN6xtW9eyWhLpGe9b2dfSGlidgKZhUlpmbc2P0bd93_VsR9858JrMoJ8WTls9maBfVmJ40PfTRrNGSKUENPh8aJCmX2C86NU0pwieNaOSEUEaDtDXPeTSlHPy_fMASvQuPg3x6V18GuID_NO_pv7Ch7wA-HIA4Gxm6OH8LuRnjhHIl9QSOLrnfofBb_87VH-_ueBUNPwRHsS2Dw</recordid><startdate>200810</startdate><enddate>200810</enddate><creator>Behm, D J</creator><creator>McAtee, J J</creator><creator>Dodson, J W</creator><creator>Neeb, M J</creator><creator>Fries, H E</creator><creator>Evans, C A</creator><creator>Hernandez, R R</creator><creator>Hoffman, K D</creator><creator>Harrison, S M</creator><creator>Lai, J M</creator><creator>Wu, C</creator><creator>Aiyar, N V</creator><creator>Ohlstein, E H</creator><creator>Douglas, S A</creator><general>Blackwell Publishing Ltd</general><general>Nature Publishing</general><general>Nature Publishing Group</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QP</scope><scope>7RV</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>5PM</scope></search><sort><creationdate>200810</creationdate><title>Palosuran inhibits binding to primate UT receptors in cell membranes but demonstrates differential activity in intact cells and vascular tissues</title><author>Behm, D J ; McAtee, J J ; Dodson, J W ; Neeb, M J ; Fries, H E ; Evans, C A ; Hernandez, R R ; Hoffman, K D ; Harrison, S M ; Lai, J M ; Wu, C ; Aiyar, N V ; Ohlstein, E H ; Douglas, S A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4815-5b7c800e4ac2ee69f7c6a9763a2999c924707e23f97f47ba01405b75277b2bb43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>ACT‐058362</topic><topic>Animals</topic><topic>antagonist</topic><topic>Associated diseases and complications</topic><topic>Biological and medical sciences</topic><topic>Cats</topic><topic>Cell Line</topic><topic>Cell Membrane - drug effects</topic><topic>Cell Membrane - metabolism</topic><topic>CHO Cells</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Diabetes. Impaired glucose tolerance</topic><topic>diabetic nephropathy</topic><topic>Endocrine pancreas. Apud cells (diseases)</topic><topic>Endocrinopathies</topic><topic>Etiopathogenesis. Screening. Investigations. Target tissue resistance</topic><topic>GPR14</topic><topic>G‐protein‐coupled receptor</topic><topic>Humans</topic><topic>Inhibitory Concentration 50</topic><topic>Kidneys</topic><topic>Macaca fascicularis</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Nephrology. Urinary tract diseases</topic><topic>palosuran</topic><topic>Pharmacology. Drug treatments</topic><topic>Quinolines - administration & dosage</topic><topic>Quinolines - pharmacology</topic><topic>Radioligand Assay</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Rats, Wistar</topic><topic>Receptors, G-Protein-Coupled - drug effects</topic><topic>Receptors, G-Protein-Coupled - metabolism</topic><topic>Research Papers</topic><topic>SB‐657510</topic><topic>Species Specificity</topic><topic>Urea - administration & dosage</topic><topic>Urea - analogs & derivatives</topic><topic>Urea - pharmacology</topic><topic>Urinary system involvement in other diseases. Miscellaneous</topic><topic>Urotensins - drug effects</topic><topic>Urotensins - metabolism</topic><topic>urotensin‐II</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Behm, D J</creatorcontrib><creatorcontrib>McAtee, J J</creatorcontrib><creatorcontrib>Dodson, J W</creatorcontrib><creatorcontrib>Neeb, M J</creatorcontrib><creatorcontrib>Fries, H E</creatorcontrib><creatorcontrib>Evans, C A</creatorcontrib><creatorcontrib>Hernandez, R R</creatorcontrib><creatorcontrib>Hoffman, K D</creatorcontrib><creatorcontrib>Harrison, S M</creatorcontrib><creatorcontrib>Lai, J M</creatorcontrib><creatorcontrib>Wu, C</creatorcontrib><creatorcontrib>Aiyar, N V</creatorcontrib><creatorcontrib>Ohlstein, E H</creatorcontrib><creatorcontrib>Douglas, S A</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Behm, D J</au><au>McAtee, J J</au><au>Dodson, J W</au><au>Neeb, M J</au><au>Fries, H E</au><au>Evans, C A</au><au>Hernandez, R R</au><au>Hoffman, K D</au><au>Harrison, S M</au><au>Lai, J M</au><au>Wu, C</au><au>Aiyar, N V</au><au>Ohlstein, E H</au><au>Douglas, S A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Palosuran inhibits binding to primate UT receptors in cell membranes but demonstrates differential activity in intact cells and vascular tissues</atitle><jtitle>British journal of pharmacology</jtitle><addtitle>Br J Pharmacol</addtitle><date>2008-10</date><risdate>2008</risdate><volume>155</volume><issue>3</issue><spage>374</spage><epage>386</epage><pages>374-386</pages><issn>0007-1188</issn><eissn>1476-5381</eissn><coden>BJPCBM</coden><abstract>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</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>18587423</pmid><doi>10.1038/bjp.2008.266</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 0007-1188 |
| ispartof | British journal of pharmacology, 2008-10, Vol.155 (3), p.374-386 |
| issn | 0007-1188 1476-5381 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2567886 |
| source | Wiley Free Content; MEDLINE; Wiley Online Library Journals Frontfile Complete; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection |
| subjects | ACT‐058362 Animals antagonist Associated diseases and complications Biological and medical sciences Cats Cell Line Cell Membrane - drug effects Cell Membrane - metabolism CHO Cells Cricetinae Cricetulus Diabetes. Impaired glucose tolerance diabetic nephropathy Endocrine pancreas. Apud cells (diseases) Endocrinopathies Etiopathogenesis. Screening. Investigations. Target tissue resistance GPR14 G‐protein‐coupled receptor Humans Inhibitory Concentration 50 Kidneys Macaca fascicularis Male Medical sciences Mice Nephrology. Urinary tract diseases palosuran Pharmacology. Drug treatments Quinolines - administration & dosage Quinolines - pharmacology Radioligand Assay Rats Rats, Sprague-Dawley Rats, Wistar Receptors, G-Protein-Coupled - drug effects Receptors, G-Protein-Coupled - metabolism Research Papers SB‐657510 Species Specificity Urea - administration & dosage Urea - analogs & derivatives Urea - pharmacology Urinary system involvement in other diseases. Miscellaneous Urotensins - drug effects Urotensins - metabolism urotensin‐II |
| title | Palosuran inhibits binding to primate UT receptors in cell membranes but demonstrates differential activity in intact cells and vascular tissues |
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