1. 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
- Author
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Kim Winborn, Sarah C. Lappin, James S. Wright, Vicky Holland, Martin J. Gunthorpe, Harshad Kantilal Rami, Andrew D. Randall, Sandra Arpino, Graham D Smith, Julie Egerton, Stephen J. Brough, Mervyn Thompson, Jeffrey C. Jerman, Sara Luis Hannan, Darren Smart, and John B. Davis
- 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 - 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.
- Published
- 2007