PT  - JOURNAL ARTICLE
AU  - Martin J. Gunthorpe
AU  - Sara Luis Hannan
AU  - Darren Smart
AU  - Jeffrey C. Jerman
AU  - Sandra Arpino
AU  - Graham D. Smith
AU  - Stephen Brough
AU  - Jim Wright
AU  - Julie Egerton
AU  - Sarah C. Lappin
AU  - Vicky A. Holland
AU  - Kim Winborn
AU  - Mervyn Thompson
AU  - Harshad K. Rami
AU  - Andrew Randall
AU  - John B. Davis
TI  - 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
AID  - 10.1124/jpet.106.116657
DP  - 2007 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1183--1192
VI  - 321
IP  - 3
4099  - http://jpet.aspetjournals.org/content/321/3/1183.short
4100  - http://jpet.aspetjournals.org/content/321/3/1183.full
SO  - J Pharmacol Exp Ther2007 Jun 01; 321
AB  - 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 Ca2+-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 (pKi = 7.6) with activity at rat (pKi = 7.5) and guinea pig (pKi = 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 (IC50 = 3 nM)-, acid (pH 5.3)-, or heat (50°C; IC50 = 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. The American Society for Pharmacology and Experimental Therapeutics