SB705498

製品コードS2773 バッチS277301

化学情報

	Synonyms	N/A	Storage (From the date of receipt)	3 years -20°C powder 1 years -80°C in solvent
	化学式	C₁₇H₁₆BrF₃N₄O
	分子量	429.23	CAS No.	501951-42-4
Solubility (25°C)*	体外	DMSO	86 mg/mL (200.35 mM)
		Ethanol	20 mg/mL (46.59 mM)
		Water	Insoluble
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

溶剤液（一定の濃度）を調合する

生物活性

製品説明	SB705498 is a TRPV1 antagonist for hTRPV1, antagonizes capsaicin, acid, and heat activation of TRPV1 with IC50 of 3 nM, 0.1 nM and 6 nM, shows a degree of voltage dependence, exhibits >100-fold selectivity for TRPV1 over TRPM8. Phase 2.
in vitro	SB705498 (0.3 nM-1 μM) potently inhibits capsaicin-induced activation of human TRPV1 expressed in 1321N1 cells or HEK293 cells with apparent pK_i 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 μM) also has no significant antagonist effect versus the close TRPV1 receptor paralog TRPV4 transiently expressed in HEK293 cells and activated using the synthetic ligand 4α-phorbol-12,13-didecanoate (10 μM). SB705498 reveals good antagonist potency against both the rat and guinea pig TRPV1. SB705498 antagonizes rat and guinea pig TRPV1 with pK_i of 7.5 and 7.3, respectively. Coapplication of 100 nM to 10 μM SB705498 to the steady 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 μM 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]

プロトコル(参考用のみ)

キナーゼアッセイ	Plate-Based FLIPR Ca²⁺ Assays.
キナーゼアッセイ	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 (λ_ex = 488 nm and λ_em = 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 4α-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.
動物実験	動物モデル	Capsaicin-induced secondary hyperalgesia model in the rat
	投薬量	3, 10 and 30 mg/kg
	投与方法	Administered via p.o.

参考

カスタマーフィードバック

: , , Biochim Biophys Acta, 2014, 1843:2730-2743.

Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：

Interaction between TRPML1 and p62 in Regulating Autophagosome-Lysosome Fusion and Impeding Neuroaxonal Dystrophy in Alzheimer's Disease [ Oxid Med Cell Longev, 2022, 2022:8096009]	PubMed: 35116093
Serum/glucocorticoid-regulated kinase 1-targeted transient receptor potential oxalate subtype 1 regulates bladder smooth muscle cell proliferation due to bladder outlet obstruction in mice via activated T cell nuclear factor transcription factor 2 [ IUBMB Life, 2022, 10.1002/iub.2605]	PubMed: 35148462
Repurposing FDA-approved drugs for anti-aging therapies. [ Biogerontology, 2016, 17(5-6):907-920]	PubMed: 27484416
Hypoximimetic activity of N-acyl-dopamines. N-arachidonoyl-dopamine stabilizes HIF-1α protein through a SIAH2-dependent pathway [Soler-Torronteras R et al. Biochim Biophys Acta, 2014, 10.1016/j.bbamcr.2014.07.005]	PubMed: 25090972

長期の保管のために-20°Cの下で製品を保ってください。

人間や獣医の診断であるか治療的な使用のためにでない。

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