GKA50
目录号 : GC38784
GKA50 是一种有效的葡萄糖激酶 (glucokinase) 激活剂 (EC50=33 nM)。GKA50 刺激小鼠胰岛和 MIN6 细胞分泌胰岛素。GKA50 对高脂高脂脂肪雌性大鼠有显著的降糖作用。
Cas No.:851884-87-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
GKA50 is a potent glucokinase activator (EC50=33 nM at 5 mM glucose). GKA50 stimulates insulin release from mouse islets of Langerhans and MIN6 cells. GKA50 shows significant glucose lowering in high fat fed female rats[1][2].
GKA50 (0.01-100 μM; 24 hours) enhances INS-1 cell proliferation with EC50values ranging from 1 to 2 μM[2].GKA50 (1.2 μM+40 μM glucose; 2-4 days) treatment reduces apoptosis induced by chronic high glucose in INS-1 cells[2].GKA50 activates human glucokinase enzymatic activity with an EC50 of 0.022 μM. GKA50 stimulates insulin secretion in the pancreatic insulinoma cell line, INS-1, with an EC50 of 0.065 μM. GKA50 reduces chronic-high-glucose-induced apoptosis via modulation of glucokinase and apoptotic protein BAD[2]. Cell Proliferation Assay[2] Cell Line: INS-1 cells (starved overnight with 3 μM glucose)
GKA50 (1-30 mg/kg; p.o.) gives significant glucose lowering in an oral glucose tolerance test[1]. Animal Model: High-fat-fed obese female Zucker (fa/fa) rats[1]
[1]. Coope GJ, et al. Predictive blood glucose lowering efficacy by Glucokinase activators in high fat fed female Zucker rats. Br J Pharmacol. 2006 Oct;149(3):328-35. [2]. McGlasson L, et al. The glucokinase activator GKA50 causes an increase in cell volume and activation of volume-regulated anion channels in rat pancreatic β-cells. Mol Cell Endocrinol. 2011 Aug 6;342(1-2):48-53.
| Cas No. | 851884-87-2 | SDF | |
| Canonical SMILES | O=C(C1=CC=C(NC(C2=CC(O[C@@H](C)CC3=CC=CC=C3)=CC(O[C@@H](C)COC)=C2)=O)N=C1)O | ||
| 分子式 | C26H28N2O6 | 分子量 | 464.51 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1528 mL | 10.764 mL | 21.5281 mL |
| 5 mM | 0.4306 mL | 2.1528 mL | 4.3056 mL |
| 10 mM | 0.2153 mL | 1.0764 mL | 2.1528 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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2.
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The glucokinase activator GKA50 causes an increase in cell volume and activation of volume-regulated anion channels in rat pancreatic β-cells
Mol Cell Endocrinol 2011 Aug 6;342(1-2):48-53.PMID:21664426DOI:10.1016/j.mce.2011.05.006.
Glucokinase plays a key role in the metabolism of glucose by pancreatic β-cells. In this study the effects of the glucokinase activator GKA50 on cell volume and electrical activity in rat β-cells were examined. One micro molar GKA50 caused an increase in β-cell volume in the presence of 4mM glucose. GKA50 also caused a depolarisation of β-cell membrane potential and increased electrical activity. These changes were associated with the activation of inward whole-cell currents, and were attenuated by the anion channel inhibitor 5-nitro-2-(3-phenylpropylamino) benzoic acid. In single channel experiments, the open probability of volume-regulated anion channels (VRAC) was increased from 0.03±0.01 to 0.19±0.04 (n=3) by the GKA50. The data suggest that a GKA50-evoked increase in glucose metabolism causes an increase in β-cell volume. This in turn activates VRAC leading to a depolarisation of the cell membrane potential.
Effects of glucokinase activators GKA50 and LY2121260 on proliferation and apoptosis in pancreatic INS-1 beta cells
Diabetologia 2009 Oct;52(10):2142-50.PMID:19641898DOI:10.1007/s00125-009-1446-0.
Aims/hypothesis: Glucokinase (GK), an enzyme that phosphorylates glucose to form glucose 6-phosphate, serves as the glucose sensor that regulates insulin secretion in beta cells. GK activators (GKAs) activate GK via binding to an allosteric site of the enzyme. GKAs increase glucose-stimulated insulin secretion and decrease blood glucose levels. Using the differentiated beta cell line INS-1, we investigated the role of GKAs in promoting beta cell growth and survival and preventing beta cell apoptosis induced by chronic exposure to high levels of glucose. Methods: Proliferation was assessed using BrdU incorporation. Apoptosis was measured using caspase-3 activity. Immunoblot analysis was used to detect protein levels and the degree of phosphorylation. Results: The GK agonists GKA50 and LY2121260 increased both cell replication and cell numbers when tested at basal levels of glucose (3 mmol/l) in INS-1 cells. GKAs promoted INS-1 cell proliferation via upregulation of insulin receptor substrate-2 and subsequent activation of protein kinase B phosphorylation. GKA50 also prevented the INS-1 cell apoptosis that was induced by chronic high glucose conditions, probably via an increase in GK protein levels and normalisation of the apoptotic protein BCL2-associated agonist of cell death (BAD) and its phosphorylation. As a result of the reduction in cell apoptosis, GKA50 prevented cell loss and maintained glucose-stimulated insulin secretion. In addition, the anti-apoptotic activity of GKA50 was significantly abrogated by other GKAs that do not inhibit apoptosis, suggesting that direct binding of GKA50 to GK is essential for its anti-apoptotic effect. Conclusion/interpretation: Our results suggest novel roles of GKAs in promoting beta cell growth and preventing chronic-hyperglycaemia-induced beta cell apoptosis. Thus, GKAs may provide novel therapeutics that increase beta cell mass to maintain euglycaemia in diabetes.
Glucose-dependent modulation of insulin secretion and intracellular calcium ions by GKA50, a glucokinase activator
Diabetes 2007 Jun;56(6):1694-702.PMID:17360975DOI:10.2337/db07-0026.
Because glucokinase is a metabolic sensor involved in the regulated release of insulin, we have investigated the acute actions of novel glucokinase activator compound 50 (GKA50) on islet function. Insulin secretion was determined by enzyme-linked immunosorbent assay, and microfluorimetry with fura-2 was used to examine intracellular Ca(2+) homeostasis ([Ca(2+)](i)) in isolated mouse, rat, and human islets of Langerhans and in the MIN6 insulin-secreting mouse cell line. In rodent islets and MIN6 cells, 1 micromol/l GKA50 was found to stimulate insulin secretion and raise [Ca(2+)](i) in the presence of glucose (2-10 mmol/l). Similar effects on insulin release were also seen in isolated human islets. GKA50 (1 micromol/l) caused a leftward shift in the glucose-concentration response profiles, and the half-maximal effective concentration (EC(50)) values for glucose were shifted by 3 mmol/l in rat islets and approximately 10 mmol/l in MIN6 cells. There was no significant effect of GKA50 on the maximal rates of glucose-stimulated insulin secretion. In the absence of glucose, GKA50 failed to elevate [Ca(2+)](i) (1 micromol/l GKA50) or to stimulate insulin release (30 nmol/l-10 micromol/l GKA50). At 5 mmol/l glucose, the EC(50) for GKA50 in MIN6 cells was approximately 0.3 micromol/l. Inhibition of glucokinase with mannoheptulose or 5-thioglucose selectively inhibited the action of GKA50 on insulin release but not the effects of tolbutamide. Similarly, 3-methoxyglucose prevented GKA50-induced rises in [Ca(2+)](i) but not the actions of tolbutamide. Finally, the ATP-sensitive K(+) channel agonist diazoxide (200 micromol/l) inhibited GKA50-induced insulin release and its elevation of [Ca(2+)](i.) We show that GKA50 is a glucose-like activator of beta-cell metabolism in rodent and human islets and a Ca(2+)-dependent modulator of insulin secretion.
Design of a potent, soluble glucokinase activator with increased pharmacokinetic half-life
Bioorg Med Chem Lett 2011 Jun 1;21(11):3467-70.PMID:21515051DOI:10.1016/j.bmcl.2011.03.093.
The continued optimization of a series of glucokinase activators is described, including attempts to understand the interplay between molecular structure and the composite parameter of unbound clearance. These studies resulted in the discovery of a new scaffold for glucokinase activators and further exploration of this scaffold led to the identification of GKA60. GKA60 maintains an excellent balance of potency and physical properties whilst possessing a significantly different, but complimentary, pre-clinical pharmacokinetic profile compared with the previously disclosed compound GKA50.
Glucose enhances rat islet function via stimulating CART expression
Biochem Biophys Res Commun 2016 Dec 2;481(1-2):84-89.PMID:27823935DOI:10.1016/j.bbrc.2016.11.012.
Cocaine- and amphetamine-regulated transcript (CART) is an anorexigenic peptide widely expressed in the central and peripheral nervous systems, as well as in endocrine cells. CART is markedly upregulated in the β-cells of several rodent models of type-2 diabetes. The stimulatory effect of exogenous CART peptide on insulin secretion is cAMP dependent. Glucose is the most important regulator of islet function. However, the role of CART in glucose-potentiated insulin secretion remains unclear. Here, our results showed that glucose time- and dose-dependently elicited CART mRNA expression in rat islets. Both the glucokinase agonist GKA50 and the long-acting GLP-1 analogue exendin-4 increased CART mRNA expression. The protein kinase A (PKA) inhibitor H89 and the inactivation of cAMP response element-binding protein (CREB) suppressed forskolin-stimulated CART mRNA expression. Furthermore, CART overexpression amplified insulin secretion from rat islets in response to glucose and forskolin, and ameliorated dexamethasone-impaired insulin secretion. These findings suggest that islet-derived CART is involved, at least in part, in high glucose-potentiated pancreatic β-cell function.