SSR240612 - Bradykinin Receptor Antagonist - 生命科學(xué)試劑 - MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemESSR240612Cat. No.: HY-15039CAS No.: 464930-42-5分式: CHClNOS分量: 793.41作靶點: Bradykinin Receptor作通路: GPCR/G Protein儲存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實驗 DMSO : 106.6 mg/mL (134.36 mM)* means

2、 soluble, but saturation unknown.Mass Solvent1 mg 5 mg 10 mg Concentration制備儲備液1 mM 1.2604 mL 6.3019 mL 12.6038 mL5 mM 0.2521 mL 1.2604 mL 2.5208 mL10 mM 0.1260 mL 0.6302 mL 1.2604 mL請根據(jù)產(chǎn)品在不同溶劑中的溶解度，選擇合適的溶劑配制儲備液，并請注意儲備液的保存式和期限。BIOLOGICAL ACTIVITY物活性 SSR240612種有效的，可服的，特異性的肽類緩激肽 B1 (bradykinin B1) 受體拮

3、抗劑，對 bradykininB1 受體（在 MRC5 細胞和表達 B1 受體的 HEK 細胞）的 Ki 值分別為 0.48 nM，0.73 nM；對 B2 受體 (在豚回腸膜和表達 B1 受體的 CHO 細胞) 的 Ki 較弱，分別為 481 nM 和 358 nM。IC50 & Target Ki: 0.48 nM (bradykinin B1 receptor, Human MRC5), 0.73 nM (bradykinin B1 receptor, Human HEK-B1), 481nM (bradykinin B2 receptor, guinea pig ileum membr

4、anes), 358 nM (bradykinin B2 receptor, Human CHO-1/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEB2) 1體外研究 SSR240612 is a potent bradykinin B1 receptor antagonist, with Kis of 0.48 nM and 0.73 nM for B2 kininreceptors of human fibroblast MRC5 and HEK cells expressing human B1 receptors, 481 nM and

5、358 nM forB1 receptors of guinea pig ileum membranes and CHO cells expressing human B1 receptor, respectively.SSR240612 inhibits inositol phosphate 1 formation with an IC50 of 1.9 nM, but shows no obvious effect oninositol phosphate-1 formation induced by BK (3 nM) activation of B2 receptor in human

6、 fibroblast MRC5 1.體內(nèi)研究 SSR240612 (10 mg/kg p.o. or 0.3, 1 mg/kg i.p.) obviously blocks the des-Arg9-BK-induced paw edema in themice. SSR240612 (10 and 30 mg/kg) reduces the duration of the late phase of paw licking in a dosedependent manner in the formalin model of inflammation in mice. SSR240612 (

7、0.3, 3, and 30 mg/kg, p.o.)treatment before capsaicin potently and non-concentration-dependently reduces the ear edema. SSR240612(0.3 mg/kg, i.v.) also suppresses the tissue destruction and neutrophil accumulation in the rat intestine, aftersplanchnic artery occlusion/reperfusion. Moreover, SSR24061

8、2 (1 and 3 mg/kg p.o.) dramacally increasesthe withdrawal latencies in the thermal hyperalgesia induced by UV irradiation in rats 1. SSR240612 inhibitstactile and cold allodynia at 3h in glucose-fed rats but had no effect in control rats with ID50s of 5.5 and 7.1mg/kg, respectively. SSR240612 shows

9、no effect on plasma glucose and insulin, insulin resistance (HOMAindex) and aortic superoxide anion production in glucose-fed rats at 10mg/kg 2.PROTOCOLKinase Assay 1 3HLys0-des-Arg9-BK binding to cell membranes is performed in binding buffer of the following composition:137 mM NaCl, 5.4 mM KCl, 1.0

10、5 mM MgCl2, 1.8 mM CaCl2, 1.2 mM NaH2PO4, 15.5 mM NaHCO3, 10 mMHEPES, 1 g/L bovine serum albumin (BSA), 140 mg/L bacitracin, and 1 M captopril, pH 7.4. Membranes areincubated for 30 min at 25C in 500 L of binding buffer containing 1 nM 3HLys0-des-Arg9-BK forcompetition curves or 0.1 to 10 nM for sat

11、uration isotherms. Filters are washed three times with 5 mL ofbinding buffer, and radioactivity is determined by liquid scintillation spectrometry. Nonspecific binding isdetermined by the addition of 1 M of unlabeled Lys0-des-Arg9BK 1.MCE has not independently confirmed the accuracy of these methods

12、. They are for reference only.Animal Mice 1Administration 1 Groups of eight male albino mice under isoflurane anesthesia receive a 20-L intraplantar injection into theright hind paw of 5 g of IL-1 in phosphate-buffered saline/0.1% BSA. Forty minutes later (T = 0), miceunder anesthesia receive a 20-L

13、 intraplantar injection in the same paw of des-Arg9-BK (10 g/paw) inwater. SSR240612 or vehicle 5% (v/v) ethanol and 5% (v/v) Tween 80 in water is administered by oral routeat the doses of 1, 3, and 10 mg/kg 1 h before des-Arg9-BK injection and by intraperitoneal route at the dosesof 0.1, 0.3, and 1

14、 mg/kg 40 min before des-Arg9-BK injection. Paw volume is measured with aplethysmometer at T = -2 h (initial measurement) and at several times after edema induction (T = 20, 40, 60,and 120 min). Paw edema volume is expressed in milliliters as the difference between the paw volume ateach time after e

15、dema induction and the initial paw volume. Results for each group are expressed as mean S.E.M. of individual paw edema volumes. Statistical analysis is performed after verification of normality andhomogeneity of variances using repeated ANOVA, then Duncans test, treated groups versus des-Arg9-BKcont

16、rol group 1.2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemERats 1SSR240612 (suspended with 0.1% Tween 80 in saline) is administered by the oral route in a volume of 20mL/kg, 2 h before the thermal hyperalgesia measurement. In the time course study, the compound isadministered at 3 mg/kg p.o. 0.08,

17、 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h before measuring the withdrawal latenciesin rats. Results are expressed in seconds as mean withdrawal latencies (s) S.E.M., and statistical analysesare performed using a two-way ANOVA followed by Dunnetts test 1.MCE has not independently confirmed the accuracy of

18、these methods. They are for reference only.REFERENCES1. Gougat J, et al. SSR240612 (2R)-2-(3R)-3-(1,3-benzodioxol-5-yl)-3-(6-methoxy-2-naphthyl)sulfonylaminopropanoyl)amino-3-(4-2R,6S)-2,6-dimethylpiperidinylmethylphenyl)-N-isopropyl-N-methylpropanamide hydrochloride, a new nonpeptide antagonist of thebradykinin B1 receptor: biochemical and pharmacological characterization. J Pharmacol Exp Ther. 2004 May;309(2):661-9.2. Dias JP, et al. The kinin B1 receptor antagonist SSR240612 reverses tactile and cold allodynia in an experimental rat