[基于4-氧-1,4-二氢肉桂碱的酪氨酸磷酸酶PTP1B和TCPTP抑制剂的表征和生物活性]。

Q3 Biochemistry, Genetics and Molecular Biology
K V Derkach, I O Zakharova, A A Bakhtyukov, V N Sorokoumov, V S Kuznetsova, A O Shpakov
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引用次数: 0

摘要

肥胖的功能障碍主要是由于组织对胰岛素和瘦素的敏感性降低。恢复的方法之一是抑制蛋白磷酸酪氨酸磷酸酶1B (PTP1B)和t细胞蛋白磷酸酪氨酸磷酸酶(TCPTP),胰岛素和瘦素信号的负调节因子。尽管这些磷酸酶抑制剂的开发取得了进展,但基于它们的商业制剂尚未开发出来,其作用机制也知之甚少。本研究旨在研究4-氧-1,4-二氢喹啉新衍生物(PI04、PI06、PI07)对PTP1B和TCPTP活性的影响,并研究其对饮食性肥胖Wistar大鼠体重和脂肪、代谢和激素参数、肝脏中磷酸酶、胰岛素和瘦素受体基因表达的影响(每日10 mg/kg/d)。PI04是两种磷酸酶(PTP1B, IC50=3.42(2.60-4.51) μM;TCPTP, IC50=4.16(3.49 ~ 4.95) μM), PI06和PI07分别优先抑制PTP1B (IC50=3.55 (2.63 ~ 4.78) μM)和TCPTP (IC50=1.45(1.18 ~ 1.78) μM)。PI04显著减少食物摄入量,体重和脂肪,减轻高血糖,葡萄糖耐量正常化,基础和葡萄糖刺激的胰岛素和瘦素水平,以及胰岛素抵抗指数。尽管有厌氧性作用,PI06和PI07的效果较差,对葡萄糖稳态和胰岛素敏感性的影响很小。PI04显著增加PTP1B和TCPTP基因的表达,降低胰岛素和瘦素受体基因的表达。PI06和PI07对这些指标影响不大。因此,PTP1B和TCPTP磷酸酶抑制剂PI04比PTP1B (PI06)和TCPTP (PI07)抑制剂更有效地恢复肥胖大鼠的代谢和激素参数。这预示着创造混合PTP1B/TCPTP抑制剂用于纠正代谢紊乱的前景。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
[Characterization and biological activity of new 4-oxo-1,4-dihydrocinnoline-based inhibitors of the tyrosine phosphatase PTP1B and TCPTP].

Functional disorders in obesity are largely due to a decrease in tissue sensitivity to insulin and leptin. One of the ways to restore it is inhibition of protein phosphotyrosine phosphatase 1B (PTP1B) and T-cell protein phosphotyrosine phosphatase (TCPTP), negative regulators of the insulin and leptin signaling. Despite progress in the development of inhibitors of these phosphatases, commercial preparations based on them have not been developed yet, and the mechanisms of action are poorly understood. The aim of the work was to study the effect of new derivatives of 4-oxo-1,4-dihydrocinnoline (PI04, PI06, PI07) on the activity of PTP1B and TCPTP, as well as to study the effect of their five-day administration (i.p., 10 mg/kg/day) to Wistar rats with diet-induced obesity on body weight and fat, metabolic and hormonal parameters, and gene expression of phosphatase and insulin and leptin receptors in the liver. It has been shown that PI04 is a mild, low selective inhibitor of both phosphatases (PTP1B, IC50=3.42(2.60-4.51) μM; TCPTP, IC50=4.16(3.49-4.95) μM), while PI06 and PI07 preferentially inhibit PTP1B (IC50=3.55 (2.63-4.78) μM) and TCPTP (IC50=1.45(1.18-1.78) μM), respectively. PI04 significantly reduced food intake, body weight and fat, attenuated hyperglycemia, normalized glucose tolerance, basal and glucose-stimulated levels of insulin and leptin, and insulin resistance index. Despite the anorexigenic effect, PI06 and PI07 were less effective, having little effect on glucose homeostasis and insulin sensitivity. PI04 significantly increased the expression of the PTP1B and TCPTP genes and decreased the expression of the insulin and leptin receptor genes. PI06 and PI07 had little effect on these indicators. Thus, PI04, the inhibitor of PTP1B and TCPTP phosphatases, restored metabolic and hormonal parameters in obese rats with greater efficiency than inhibitors of PTP1B (PI06) and TCPTP (PI07). This indicates the prospect of creating mixed PTP1B/TCPTP inhibitors for correction of metabolic disorders.

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来源期刊
Biomeditsinskaya khimiya
Biomeditsinskaya khimiya Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)
CiteScore
1.30
自引率
0.00%
发文量
49
期刊介绍: The aim of the Russian-language journal "Biomeditsinskaya Khimiya" (Biomedical Chemistry) is to introduce the latest results obtained by scientists from Russia and other Republics of the Former Soviet Union. The Journal will cover all major areas of Biomedical chemistry, including neurochemistry, clinical chemistry, molecular biology of pathological processes, gene therapy, development of new drugs and their biochemical pharmacology, introduction and advertisement of new (biochemical) methods into experimental and clinical medicine etc. The Journal also publish review articles. All issues of journal usually contain invited reviews. Papers written in Russian contain abstract (in English).
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