含龙脑烯基的苄氧基苯基丙酸衍生物作为游离脂肪酸受体1激动剂的体外和体内研究

Bornyl-Containing Derivatives of Benzyloxyphenylpropanoic Acid as FFAR1 Agonists: In Vitro and In Vivo Studies.

作者信息

Pon'kina Darya A, Kuranov Sergey O, Marenina Mariya K, Meshkova Yulia V, Zhukova Nataliya A, Khvostov Mikhail V, Luzina Olga A, Tolstikova Tatiana G, Salakhutdinov Nariman F

机构信息

N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., Novosibirsk 630090, Russia.

出版信息

Pharmaceutics. 2023 Jun 7;15(6):1670. doi: 10.3390/pharmaceutics15061670.

DOI:10.3390/pharmaceutics15061670

PMID:37376118

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10300945/

Abstract

Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases worldwide. Several classes of hypoglycemic drugs are used to treat it, but various side effects limit their clinical use. Consequently, the search for new anti-diabetic agents remains an urgent task for modern pharmacology. In this investigation, we examined the hypoglycemic effects of bornyl-containing benzyloxyphenylpropanoic acid derivatives (QS-528 and QS-619) in a diet-induced model of T2DM. Animals were given the tested compounds per os at a dose of 30 mg/kg for 4 weeks. At the end of the experiment, compound QS-619 demonstrated a hypoglycemic effect, while QS-528 showed hepatoprotection. In addition, we performed a number of in vitro and in vivo experiments to study the presumed mechanism of action of the tested agents. Compound QS-619 was determined to activate the free fatty acid receptor-1 (FFAR1) similarly to the reference agonist GW9508 and its structural analogue QS-528. Both agents also increased insulin and glucose-dependent insulinotropic polypeptide concentrations in CD-1 mice. Our results indicate that QS-619 and QS-528 are probably full FFAR1 agonists.

摘要

2型糖尿病（T2DM）是全球最常见的慢性病之一。几类降糖药物被用于治疗该病，但各种副作用限制了它们的临床应用。因此，寻找新型抗糖尿病药物仍然是现代药理学的一项紧迫任务。在本研究中，我们在饮食诱导的T2DM模型中检测了含龙脑的苄氧基苯基丙酸衍生物（QS-528和QS-619）的降糖作用。以30 mg/kg的剂量给动物口服受试化合物，持续4周。在实验结束时，化合物QS-619表现出降糖作用，而QS-528显示出肝脏保护作用。此外，我们进行了一些体外和体内实验，以研究受试药物的推测作用机制。确定化合物QS-619与参考激动剂GW9508及其结构类似物QS-528一样，能激活游离脂肪酸受体-1（FFAR1）。两种药物还提高了CD-1小鼠体内胰岛素和葡萄糖依赖性促胰岛素多肽的浓度。我们的结果表明，QS-619和QS-528可能是完全的FFAR1激动剂。