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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
- Source :
- Journal of Pharmacology and Experimental Therapeutics. 321:1183-1192
- Publication Year :
- 2007
- Publisher :
- American Society for Pharmacology & Experimental Therapeutics (ASPET), 2007.
-
Abstract
- 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.
- Subjects :
- Hot Temperature
Patch-Clamp Techniques
Pyrrolidines
Guinea Pigs
TRPV1
TRPV Cation Channels
Pharmacology
Transfection
Binding, Competitive
Cell Line
Membrane Potentials
chemistry.chemical_compound
In vivo
Animals
Humans
Urea
Calcium Signaling
Patch clamp
Receptor
Cells, Cultured
Calcium signaling
Neurons
Dose-Response Relationship, Drug
Molecular Structure
Antagonist
Hydrogen-Ion Concentration
Rats
Electrophysiology
chemistry
Capsaicin
Competitive antagonist
Molecular Medicine
Acids
Subjects
Details
- ISSN :
- 15210103 and 00223565
- Volume :
- 321
- Database :
- OpenAIRE
- Journal :
- Journal of Pharmacology and Experimental Therapeutics
- Accession number :
- edsair.doi.dedup.....519bdcb9b1541b2a29cae2ecf14a8d24