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SB705498 Europäischer Partner

ArtNr S2773-200
Hersteller Selleckchem
CAS-Nr. 501951-42-4
Menge 200 mg
Quantity options 10 mg 1 g 10 g 10 mM/1 ml 200 mg 5 mg 50 mg 5 g
Kategorie
Typ Inhibitors
Specific against other
ECLASS 10.1 32160490
ECLASS 11.0 32160490
UNSPSC 12000000
Alias hTRPV1,hTRPV1,TRPV
Similar products SB705498
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Storage Conditions
2 years -20°C Powder, 2 weeks 4°C in DMSO, 2 months -80°C in DMSO
Molecular Weight
429, 23
Administration
Administered via p.o.
Animal Models
Capsaicin-induced secondary hyperalgesia model in the rat
Clinical Trials
A Phase II clinical trial for SB705498 has been completed in the treatment of non-allergic rhinitis.
Dosages
3, 10 and 30 mg/kg
IC50
7.1 (pIC50), 7.1 (pIC50), 7.1 (pIC50), 7.1 (pIC50), 7.1 (pIC50), 7.1 (pIC50)
In vitro
SB705498 (0.3 nM-1 uM) potently inhibits capsaicin-induced activation of human TRPV1 expressed in 1321N1 cells or HEK293 cells with apparent pKi of 7.5 or 7.6, respectively. Coapplication of 100 nM SB705498 rapidly, completely and reversibly inhibits hTRPV1 expressed in HEK293 cells. SB705498, has no significant effect on endogenous [Ca2+] responses in HEK293 cells produced by muscarinic acetylcholine receptor activation with carbachol or store-operated channel-mediated Ca2+ entry after depletion of intracellular stores with the Ca2+ pump inhibitor thapsigargin. SB705498 (10 pM–1 uM) also has no significant antagonist effect versus the close TRPV1 receptor paralog TRPV4 transiently expressed in HEK293 cells and activated using the synthetic ligand 4alpha-phorbol-12, 13-didecanoate (10 uM). SB705498 reveals good antagonist potency against both the rat and guinea pig TRPV1. SB705498 antagonizes rat and guinea pig TRPV1 with pKi of 7.5 and 7.3, respectively. Coapplication of 100 nM to 10 uM SB705498 to the stey state of a maintained capsaicin response leads to rapid and complete inhibition of hTRPV1 at -70 mV. SB705498 inhibits capsaicin-mediated activation of hTRPV1 with IC50 of 3 nM and 17 nM at positive and negative holding potentials (-70 mV and + 70 mV), respectively. Coapplication of 1 uM SB705498 to the plateau period of the response produces complete and reversible inhibition of the TRPV1-mediated conductance. [1] SB705498 shows approximately equal activity versus multiple and diverse chemical and physical modes of TRPV1 receptor activation. SB705498 shows little or no activity versus a wide range of ion channels, receptors and enzymes. SB705498 produces full blockade of heat as well as pH activation of hTRPV1. [2]
In vivo
SB705498 exhibits potent and reversible blockade against the multiple modes of TRPV1 activation, namely the vanilloid (capsaicin), heat- and acid-mediated activation of the receptor. SB705498 displays excellent activity at 10 and 30 mg/kg po with good reversal of allodynia. SB705498 is also shown to give 80% reversal of allodynia in the guinea pig FCA model at 10 mg/kg p.o.. [2]
Kinase Assay
Plate-Based FLIPR Ca2+ Assays., One day before the assay is performed, HEK293 cells expressing recombinant human, rat, or guinea pig TRPV1 or TRPV1 expressed in 1321N1 astrocytoma cells, are plated onto 96-well, black-walled, assay plates, at a density of 2.5, 104 cells/well. These plates are then returned to the cell culture incubator until 2.5 hours before the assay when they are removed, and the cells are loaded with the Ca2+ reporter dye Fluo3-AM for 2 hours at room temperature. After this, the cells are washed four times with Tyrode's medium, before being incubated for 30 min at 25 C with either Tyrode's medium alone (control) or Tyrode's medium containing SB705498 at a range of different concentrations. The plates are then placed into a FLIPR to monitor fluorescence (lambdaex = 488 nm and lambdaem = 540 nm) before and after the addition of capsaicin (N.B.: unless otherwise stated, antagonist potency is determined versus an EC80 concentration of capsaicin that is determined empirically on the day of the experiment). Similar methods are also used for the study of the 4alpha-phorbol-12, 13-didecanoate-mediated activation of TRPV4 transiently expressed in HEK293 cells, the endogenous Ca2+ response to carbachol or store depletion-induced Ca2+ entry in HEK293 cells, or capsaicin responses of rat dorsal root ganglion neurons in culture. For Schild analysis (competition) FLIPR experiments, the procedures used are broadly similar, except that a BacMam-mediated transfection of HEK293 cells is used (see above) and experiments are conducted using Fluo4-AM. Assay plates for study are incubated at room temperature for 2 hours before being washed with Tyrode's medium, incubated for 15 min with either Tyrode's medium alone (control) or Tyrode's medium containing SB705498 at a range of different concentrations, and assesses in the FLIPR for responses evoked by the application of capsaicin. Experiments to assess the inhibitory action of SB705498 versus the acid-mediated activation of TRPV1 stably expressed in HEK293 cells uses a “desensitization protocol†to remove the contribution of endogenous ASIC currents in these cells to the signal measured. Briefly, cells are preincubated in an extracellular solution at pH 6.7 for 30 min before addition of HCl to achieve a shift to pH 5, a concentration sufficient to achieve robust activation of TRPV1. The precise concentration of HCl required is calculated on the day of the experiment by titration.
Solubility (25C)
DMSO 86 mg/mL, Water <1 mg/mL, Ethanol 20 mg/mL
Information
SB705498 is a TRPV1 antagonist for hTRPV1 with pIC50 and pKi of 7.1 and 7.6 in HEK293 cells.
Chemical Name
(R)-1-(2-bromophenyl)-3-(1-(5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)urea

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Menge: 200 mg
Lieferbar: In stock
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