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SSR240612 Sale

目录号 : GC19339

SSR240612是一种新的、有效的、具有口服活性的特异性非肽慢激肽B1受体拮抗剂,可抑制Lys0-desAr9-BK (10nM) 诱导的人成纤维细胞MRC5中肌醇单磷酸的形成,IC50为1.9nM。

SSR240612 Chemical Structure

Cas No.:464930-42-5

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5mg
¥1,712.00
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10mg
¥2,667.00
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25mg
¥5,397.00
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50mg
¥8,190.00
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100mg
¥12,968.00
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Sample solution is provided at 25 µL, 10mM.

Description

SSR240612 is a new, potent, and orally active specific non-peptide bradykinin B1 receptor antagonist, which inhibited Lys0-desAr9-BK (10nM)-induced inositol monophosphate formation in human fibroblast MRC5, with an IC50 of 1.9nM[1]. Bradykinin B1 Receptor (B1R) is a G-protein-coupled receptor with low expression level in normal tissues, but it can be induced to express in pathological states such as inflammation, diabetes, ischemia/reperfusion injury, and participate in inflammation and pain signal transmission[2]. SSR240612 displaced the binding of [3H]Lys0-des-Arg9-BK to the B1 receptors in human fibroblast MRC5 and to recombinant human B1 receptor expressed in human embryonic kidney cells with inhibition constants (Ki ) of 0.48 and 0.73nM, respectively. The affinity of SSR240612 for B2 receptors labeled with [3H]BK was much lower with a Ki of 481nM for guinea pig ileum membranes and a Ki of 358nM for membrane preparations of CHO cells expressing human B2 receptors[1]. SSR240612 is usually used for research in inflammatory, immune, and metabolic diseases[3][4][5].

In vitro, treatment of M. tuberculosis-infected RAW 264.7 cells with SSR240612 (10μM) for 4 days displayed a marked inhibitory effect on CFU counts[6].

In vivo, oral administration of SSR240612 (10 and 30mg/kg) for 3h blocked tactile and cold allodynia without affecting plasma glucose and insulin, insulin resistance (HOMA index) and aortic superoxide anion production in glucose-fed rat compared with control rat[7].

References:
[1] Gougat, J., Ferrari, B., Sarran, L., Planchenault, C., Poncelet, M., Maruani, J., Alonso, R., Cudennec, A., Croci, T., Guagnini, F., Urban-Szabo, K., Martinolle, J. P., Soubrié, P., Finance, O., & Le Fur, G. (2004). SSR240612 [(2R)-2-[((3R)-3-(1,3-benzodioxol-5-yl)-3-[[(6-methoxy-2-naphthyl)sulfonyl]amino]propanoyl)amino]-3-(4-[[2R,6S)-2,6-dimethylpiperidinyl]methyl]phenyl)-N-isopropyl-N-methylpropanamide hydrochloride], a new nonpeptide antagonist of the bradykinin B1 receptor: biochemical and pharmacological characterization. The Journal of pharmacology and experimental therapeutics, 309(2), 661–669.
[2] Campos, M. M., Leal, P. C., Yunes, R. A., & Calixto, J. B. (2006). Non-peptide antagonists for kinin B1 receptors: new insights into their therapeutic potential for the management of inflammation and pain. Trends in pharmacological sciences, 27(12), 646–651.
[3] Tidjane, N., Hachem, A., Zaid, Y., Merhi, Y., Gaboury, L., Girolami, J. P., & Couture, R. (2015). A primary role for kinin B1 receptor in inflammation, organ damage, and lethal thrombosis in a rat model of septic shock in diabetes. European journal of inflammation, 13(1), 40–52.
[4] Costa, R., Fernandes, E. S., Menezes-de-Lima, O., Jr, Campos, M. M., & Calixto, J. B. (2006). Effect of novel selective non-peptide kinin B(1) receptor antagonists on mouse pleurisy induced by carrageenan. Peptides, 27(11), 2967–2975.
[5] El Akoum, S., Haddad, Y., & Couture, R. (2017). Impact of pioglitazone and bradykinin type 1 receptor antagonist on type 2 diabetes in high-fat diet-fed C57BL/6J mice. Obesity science & practice, 3(3), 352–362.
[6] Rodrigues-Junior, V. S., Pail, P. B., Villela, A. D., Falcão, V. C. A., Dadda, A. S., Abbadi, B. L., Pesquero, J. B., Santos, D. S., Basso, L. A., & Campos, M. M. (2018). Effect of the bradykinin 1 receptor antagonist SSR240612 after oral administration in Mycobacterium tuberculosis-infected mice. Tuberculosis (Edinburgh, Scotland), 109, 1–7.
[7] Dias, J. P., Ismael, M. A., Pilon, M., de Champlain, J., Ferrari, B., Carayon, P., & Couture, R. (2007). The kinin B1 receptor antagonist SSR240612 reverses tactile and cold allodynia in an experimental rat model of insulin resistance. British journal of pharmacology, 152(2), 280–287.

SSR240612是一种新的、有效的、具有口服活性的特异性非肽慢激肽B1受体拮抗剂,可抑制Lys0-desAr9-BK (10nM) 诱导的人成纤维细胞MRC5中肌醇单磷酸的形成,IC50为1.9nM[1]。缓激肽B1受体(Bradykinin B1 Receptor, B1R)是一种G蛋白偶联受体,在正常组织中表达水平较低,但在炎症、糖尿病、缺血/再灌注损伤等病理状态下可诱导表达,参与炎症和疼痛信号传递[2]。SSR240612抑制了[3H]Lys0-des-Arg9-BK与人成纤维细胞MRC5中B1受体和人胚胎肾细胞中表达的重组人B1受体的结合,抑制常数(Ki)分别为0.48和0.73nM。SSR240612对[3H]BK标记的B2受体的亲和力更低,对豚鼠回肠膜的Ki为481nM,对表达人B2受体的CHO细胞的膜制剂的Ki为358nM[1]。SSR240612通常用于炎症、免疫和代谢性疾病的研究[3][4][5]

在体外,10μM SSR240612 处理感染结核分支杆菌的RAW 264.7细胞4天可显著抑制CFU计数[6]

在体内,与对照大鼠相比,口服SSR240612(10和30mg/kg) 3h可阻断葡萄糖喂养大鼠的触觉和冷痛觉,而不影响血糖和胰岛素、胰岛素抵抗(HOMA指数)和主动脉超氧阴离子生成[7]

实验参考方法

Cell experiment [1]:

Cell lines

RAW 264.7 cells

Preparation Method

RAW 264.7 cells were infected with M. tuberculosis H37Rv for 3 h, followed by washing extracellular bacteria. The cells were then treated with the tested substances in DMEM medium: BK (3nM), des-Arg9 -BK (30nM), HOE-140 (1μM), and SSR240612 (10μM). After 4 days, macrophages were then lysed with 0.025% SDS, and these suspensions were diluted and plated on Middlebrook 7H10 Agar containing OADC, prior to CFU counting.

Reaction Conditions

10μM; 4 days

Applications

SSR240612 displayed a marked inhibitory effect on CFU counts.

Animal experiment [2]:

Animal models

Young male Sprague–Dawley rats

Preparation Method

SSR240612 was administered orally to rats fed D-glucose for 12 weeks, which displayed consistent symptoms of sensory abnormalities. The effects of four doses (0.3, 3.0, 10 and 30mg/kg) of SSR240612 were determined on allodynia at 1, 3, 6, 24, and 48h post-gavage. SSR240612 was administered orally at the dose of 10mg/kg to rats treated for 12 weeks with glucose (n= 8). Rats were fasted overnight and killed by CO2 asphyxia at 6h post-gavage, and then the blood and thoracic aorta were collected for the measurement of plasma levels of glucose and insulin and the determination of superoxide anion, respectively.

Dosage form

0.3, 3.0, 10 and 30mg/kg;1, 3, 6, 24, and 48h; p.o.

Applications

SSR240612 blocked tactile and cold allodynia at 3h (ID50 = 5.5 and 7.1mg/kg,respectively) in glucose-fed rats but had no effect in control rats. The antagonist (10mg/kg) had no effect on plasma glucose and insulin, insulin resistance (HOMA index) and aortic superoxide anion production in glucose-fed rats.

References:
[1] Rodrigues-Junior, V. S., Pail, P. B., Villela, A. D., Falcão, V. C. A., Dadda, A. S., Abbadi, B. L., Pesquero, J. B., Santos, D. S., Basso, L. A., & Campos, M. M. (2018). Effect of the bradykinin 1 receptor antagonist SSR240612 after oral administration in Mycobacterium tuberculosis-infected mice. Tuberculosis (Edinburgh, Scotland), 109, 1–7.
[2] Dias, J. P., Ismael, M. A., Pilon, M., de Champlain, J., Ferrari, B., Carayon, P., & Couture, R. (2007). The kinin B1 receptor antagonist SSR240612 reverses tactile and cold allodynia in an experimental rat model of insulin resistance. British journal of pharmacology, 152(2), 280–287.

化学性质

Cas No. 464930-42-5 SDF
Canonical SMILES O=S(N[C@@H](C1=CC=C2C(OCO2)=C1)CC(N[C@@H](C(N(C)C(C)C)=O)CC3=CC=C(CN([C@@H]4C)[C@H](CCC4)C)C=C3)=O)(C5=CC(C=CC(OC)=C6)=C6C=C5)=O.Cl[H]
分子式 C42H53ClN4O7S 分子量 793.41
溶解度 DMSO : ≥ 106.6 mg/mL (134.36 mM) 储存条件 Store at -20°C
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1 mM 1.2604 mL 6.3019 mL 12.6038 mL
5 mM 0.2521 mL 1.2604 mL 2.5208 mL
10 mM 0.126 mL 0.6302 mL 1.2604 mL
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