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.

摘要: Vanilloid receptor-1 (TRPV1) is a nonselective cation channel, predominantly expressed by sensory neurons, which plays key role in the detection of noxious painful stimuli such as capsaicin, acid, and heat. TRPV1 antagonists may represent novel therapeutic agents for treatment range conditions including chronic pain, migraine, gastrointestinal disorders. Here we describe vitro pharmacology N-(2-bromophenyl)-N'-[((R)-1-(5-trifluoromethyl-2-pyridyl)pyrrolidin-3-yl)]urea (SB-705498), antagonist identified lead optimization N-(2-bromophenyl)-N'-[2-[ethyl(3-methylphenyl)amino]ethyl]urea (SB-452533), has now entered clinical trials. Using Ca(2+)-based fluorometric imaging plate reader (FLIPR) assay, SB-705498 was shown to be potent competitive capsaicin-mediated activation human receptor (pK(i) = 7.6) with activity at rat 7.5) guinea pig 7.3) orthologs. Whole-cell patch-clamp electrophysiology used confirm extend these findings, demonstrating that can potently inhibit multiple modes relevant pathophysiological vivo: caused rapid reversible inhibition capsaicin (IC(50) 3 nM)-, acid (pH 5.3)-, or heat (50 degrees C; IC(50) 6 nM)-mediated (at -70 mV). Interestingly, also showed degree voltage dependence, suggesting an effective enhancement action negative potentials those might encountered neurons vivo. The selectivity defined broad profiling other cellular assays it little no versus wide ion channels, receptors, enzymes. therefore represents selective multimodal antagonist, pharmacological profile contributed its definition suitable drug candidate development.