Source:http://linkedlifedata.com/resource/pubmed/id/17392405
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
3
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| pubmed:dateCreated |
2007-5-15
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| pubmed:abstractText |
Vanilloid receptor-1 (TRPV1) is a nonselective cation channel, predominantly expressed by sensory neurons, which plays a key role in the detection of noxious painful stimuli such as capsaicin, acid, and heat. TRPV1 antagonists may represent novel therapeutic agents for the treatment of a range of conditions including chronic pain, migraine, and gastrointestinal disorders. Here we describe the in vitro pharmacology of N-(2-bromophenyl)-N'-[((R)-1-(5-trifluoromethyl-2-pyridyl)pyrrolidin-3-yl)]urea (SB-705498), a novel TRPV1 antagonist identified by lead optimization of N-(2-bromophenyl)-N'-[2-[ethyl(3-methylphenyl)amino]ethyl]urea (SB-452533), which has now entered clinical trials. Using a Ca(2+)-based fluorometric imaging plate reader (FLIPR) assay, SB-705498 was shown to be a potent competitive antagonist of the capsaicin-mediated activation of the human TRPV1 receptor (pK(i) = 7.6) with activity at rat (pK(i) = 7.5) and guinea pig (pK(i) = 7.3) orthologs. Whole-cell patch-clamp electrophysiology was used to confirm and extend these findings, demonstrating that SB-705498 can potently inhibit the multiple modes of receptor activation that may be relevant to the pathophysiological role of TRPV1 in vivo: SB-705498 caused rapid and reversible inhibition of the capsaicin (IC(50) = 3 nM)-, acid (pH 5.3)-, or heat (50 degrees C; IC(50) = 6 nM)-mediated activation of human TRPV1 (at -70 mV). Interestingly, SB-705498 also showed a degree of voltage dependence, suggesting an effective enhancement of antagonist action at negative potentials such as those that might be encountered in neurons in vivo. The selectivity of SB-705498 was defined by broad receptor profiling and other cellular assays in which it showed little or no activity versus a wide range of ion channels, receptors, and enzymes. SB-705498 therefore represents a potent and selective multimodal TRPV1 antagonist, a pharmacological profile that has contributed to its definition as a suitable drug candidate for clinical development.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Acids,
http://linkedlifedata.com/resource/pubmed/chemical/Capsaicin,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrrolidines,
http://linkedlifedata.com/resource/pubmed/chemical/SB 705498,
http://linkedlifedata.com/resource/pubmed/chemical/TRPV Cation Channels,
http://linkedlifedata.com/resource/pubmed/chemical/TRPV1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Urea
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| pubmed:status |
MEDLINE
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| pubmed:month |
Jun
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| pubmed:issn |
0022-3565
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| pubmed:author |
pubmed-author:ArpinoSandraS,
pubmed-author:BroughStephenS,
pubmed-author:DavisJohn BJB,
pubmed-author:EgertonJulieJ,
pubmed-author:GunthorpeMartin JMJ,
pubmed-author:HannanSara LuisSL,
pubmed-author:HollandVicky AVA,
pubmed-author:JermanJeffrey CJC,
pubmed-author:LappinSarah CSC,
pubmed-author:RamiHarshad KHK,
pubmed-author:RandallAndrewA,
pubmed-author:SmartDarrenD,
pubmed-author:SmithGraham DGD,
pubmed-author:ThompsonMervynM,
pubmed-author:WinbornKimK,
pubmed-author:WrightJimJ
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| pubmed:issnType |
Print
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| pubmed:volume |
321
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
1183-92
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| pubmed:dateRevised |
2011-2-1
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| pubmed:meshHeading |
pubmed-meshheading:17392405-Acids,
pubmed-meshheading:17392405-Animals,
pubmed-meshheading:17392405-Binding, Competitive,
pubmed-meshheading:17392405-Calcium Signaling,
pubmed-meshheading:17392405-Capsaicin,
pubmed-meshheading:17392405-Cell Line,
pubmed-meshheading:17392405-Cells, Cultured,
pubmed-meshheading:17392405-Dose-Response Relationship, Drug,
pubmed-meshheading:17392405-Electrophysiology,
pubmed-meshheading:17392405-Guinea Pigs,
pubmed-meshheading:17392405-Hot Temperature,
pubmed-meshheading:17392405-Humans,
pubmed-meshheading:17392405-Hydrogen-Ion Concentration,
pubmed-meshheading:17392405-Membrane Potentials,
pubmed-meshheading:17392405-Molecular Structure,
pubmed-meshheading:17392405-Neurons,
pubmed-meshheading:17392405-Patch-Clamp Techniques,
pubmed-meshheading:17392405-Pyrrolidines,
pubmed-meshheading:17392405-Rats,
pubmed-meshheading:17392405-TRPV Cation Channels,
pubmed-meshheading:17392405-Transfection,
pubmed-meshheading:17392405-Urea
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| pubmed:year |
2007
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| pubmed:articleTitle |
Characterization of SB-705498, a potent and selective vanilloid receptor-1 (VR1/TRPV1) antagonist that inhibits the capsaicin-, acid-, and heat-mediated activation of the receptor.
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| pubmed:affiliation |
Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, Essex, UK. martin_j_gunthorpe@gsk.com
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| pubmed:publicationType |
Journal Article
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