Tifenazoxide
(Synonyms: NN414) 目录号 : GC38952Tifenazoxide (NN414) 是一种有效的,口服活性的 SUR1/Kir6.2 选择性 KATP 通道开放剂。Tifenazoxide 具有抗糖尿病作用,可以抑制葡萄糖刺激的胰岛素在体内和体外的释放,并对葡萄糖稳态具有有益作用。
Cas No.:279215-43-9
Sample solution is provided at 25 µL, 10mM.
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Tifenazoxide (NN414) is a potent, orally active and SUR1/Kir6.2 selective KATP channels opener. Tifenazoxide has antidiabetic effect, can inhibit glucose stimulated insulin release in vitro and in vivo, and has a beneficial effect on glucose homeostasis[1][2].
Tifenazoxide (NN414) hyperpolarises βTC3 cell membranes, and inhibits insulin release from βTC6, from isolated rat islets and from human islets at least a 100-fold more potent than Diazoxide[2]. The EC50 values for Tifenazoxide and diazoxide are 0.45 and 31 µM, respectively in the patch-clamp assay. Tifenazoxide (100 µM) activates Kir6.2/SUR1 channels, but not Kir6.2/SUR2A or Kir6.2/SUR2 channels, expressed in Xenopus oocytes both in whole-cell and inside-out macropatch recordings[2]. Tifenazoxide is a potent inhibitor of glucose stimulated insulin release from βTC6 cells (IC50 = 0.15 µM)[1].
Tifenazoxide (NN414; 1.5 mg/kg; oral administration; twice daily; for 3 weeks; male VDF Zucker (fa/fa) rat) treatment for 3 weeks in VDF rats reduces basal hyperglycemia, improves glucose tolerance, and reduces hyperinsulinemia during an oral glucose tolerance test (OGTT) and improves insulin secretory responsiveness ex vivo[1]. Animal Model: Male Vancouver diabetic fatty (VDF) Zucker rat[1]
[1]. Carr RD, et al. NN414, a SUR1/Kir6.2-selective potassium channel opener, reduces blood glucose and improves glucose tolerance in the VDF Zucker rat. Diabetes. 2003 Oct;52(10):2513-8. [2]. Hansen JB. Towards selective Kir6.2/SUR1 potassium channel openers, medicinal chemistry and therapeutic perspectives. Curr Med Chem. 2006;13(4):361-76.
Cas No. | 279215-43-9 | SDF | |
别名 | NN414 | ||
Canonical SMILES | O=S1(N=C(NC2=C1SC(Cl)=C2)NC3(CC3)C)=O | ||
分子式 | C9H10ClN3O2S2 | 分子量 | 291.78 |
溶解度 | DMSO : 100 mg/mL (342.72 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
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5 mM | 0.6854 mL | 3.4272 mL | 6.8545 mL |
10 mM | 0.3427 mL | 1.7136 mL | 3.4272 mL |
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Diabetes reduces β-cell mitochondria and induces distinct morphological abnormalities, which are reproducible by high glucose in vitro with attendant dysfunction
Islets 2012 May-Jun;4(3):233-42.PMID:22854606DOI:10.4161/isl.20516.
We investigated the impact of a diabetic state with hyperglycemia on morphometry of β cell mitochondria and modifying influence of a K (+) -ATP channel opener and we related in vivo findings with glucose effects in vitro. For in vivo experiments islets from syngeneic rats were transplanted under the kidney capsule to neonatally streptozotocin-diabetic or non-diabetic recipients. Diabetic recipients received vehicle, or Tifenazoxide (NN414), intragastrically for 9 weeks. Non-diabetic rats received vehicle. Transplants were excised 7 d after cessation of treatment (wash-out) and prepared for electron microscopy. Morphological parameters were measured from approx. 25,000 mitochondria. Rat islets were cultured in vitro for 2-3 weeks at 27 or 11 (control) mmol/l glucose. Transplants to diabetic rats displayed decreased numbers of mitochondria (-31%, p < 0.05), increased mitochondrial volume and increased mitochondrial outer surface area, p < 0.001. Diabetes increased variability in mitochondrial size with frequent appearance of mega-mitochondria. Tifenazoxide partly normalized diabetes-induced effects, and mega-mitochondria disappeared. Long-term culture of islets at 27 mmol/l glucose reproduced the in vivo morphological abnormalities. High-glucose culture was also associated with reduced ATP and ADP contents, reduced oxygen consumption, reduced signaling by MitoTracker Red and reduction of mitochondrial proteins (complexes I-IV), OPA 1 and glucose-induced insulin release. We conclude that (1) a long-term diabetic state leads to a reduced number of mitochondria and to distinct morphological abnormalities which are replicated by high glucose in vitro; (2) the morphological abnormalities are coupled to dysfunction; (3) K (+) -ATP channel openers may have potential to partly reverse glucose-induced effects.