金雀花堿，一种有潜力的口服小分子胰高血糖素样肽-1 受体激动剂，可降低血糖并改善非酒精性脂肪性肝炎。
Cinchonine, a Potential Oral Small-Molecule Glucagon-Like Peptide-1 Receptor Agonist, Lowers Blood Glucose and Ameliorates Non-Alcoholic Steatohepatitis.
机构信息
Department of Pharmacology, Shanxi Medical University, Taiyuan, 030001, People's Republic of China.
Department of Endocrinology, First Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, 030001, People's Republic of China.
出版信息
Drug Des Devel Ther. 2023 May 11;17:1417-1432. doi: 10.2147/DDDT.S404055. eCollection 2023.
PURPOSE
The glucagon-like peptide-1 receptor (GLP-1R) is an effective therapeutic target for type 2 diabetes mellitus (T2DM) and non-alcoholic steatohepatitis (NASH). Research has focused on small-molecule GLP-1R agonists because of their ease of use in oral formulations and improved patient compliance. However, no small-molecule GLP-1R agonists are currently available in the market. We aimed to screen for a potential oral small-molecule GLP-1R agonist and evaluated its effect on blood glucose and NASH.
METHODS
The Connectivity map database was used to screen for candidate small-molecule compounds. Molecular docking was performed using SYBYL software. Rat pancreatic islets were incubated in different concentrations glucose solutions, with cinchonine or Exendin (9-39) added to determine insulin secretion levels. C57BL/6 mice, GLP-1R mice and hGLP-1R mice were used to conduct oral glucose tolerance test. In addition, we fed ob/ob mice with the GAN diet to induce the NASH model. Cinchonine (50 mg/kg or 100 mg/kg) was administered orally twice daily to the mice. Serum liver enzymes were measured using biochemical analysis. Liver tissues were examined using Hematoxylin-eosin staining, Oil Red O staining and Sirius Red staining.
RESULTS
Based on the small intestinal transcriptome of geniposide, a recognized small-molecule GLP-1R agonist, we identified that cinchonine exerted GLP-1R agonist-like effects. Cinchonine had a good binding affinity for GLP-1R. Cinchonine promoted glucose-dependent insulin secretion, which could be attenuated significantly by Exendin (9-39), a specific GLP-1R antagonist. Moreover, cinchonine could reduce blood glucose in C57BL/6 and hGLP-1R mice, an effect that could be inhibited with GLP-1R knockout. In addition, cinchonine reduced body weight gain and food intake in ob/ob-GAN NASH mice dose-dependently. 100 mg/kg cinchonine significantly improved liver function by reducing the ALT, ALP and LDH levels. Importantly, 100 mg/kg cinchonine ameliorated hepatic steatosis and fibrosis in NASH mice.
CONCLUSION
Cinchonine, a potential oral small-molecule GLP-1R agonist, could reduce blood glucose and ameliorate NASH, providing a strategy for developing small-molecule GLP-1R agonists.
目的
胰高血糖素样肽-1 受体（GLP-1R）是 2 型糖尿病（T2DM）和非酒精性脂肪性肝炎（NASH）的有效治疗靶点。由于其易于口服制剂使用和改善患者依从性，因此研究集中在小分子 GLP-1R 激动剂上。然而，目前市场上尚无小分子 GLP-1R 激动剂。我们旨在筛选一种潜在的口服小分子 GLP-1R 激动剂，并评估其对血糖和 NASH 的影响。
方法
使用 Connectivity map 数据库筛选候选小分子化合物。使用 SYBYL 软件进行分子对接。将大鼠胰岛在不同浓度葡萄糖溶液中孵育，并加入辛可宁或 Exendin（9-39）以确定胰岛素分泌水平。使用 C57BL/6 小鼠、GLP-1R 小鼠和 hGLP-1R 小鼠进行口服葡萄糖耐量试验。此外，我们用 GAN 饮食喂养 ob/ob 小鼠以诱导 NASH 模型。辛可宁（50mg/kg 或 100mg/kg）每天口服给药两次。使用生化分析测量血清肝酶。使用苏木精-伊红染色、油红 O 染色和天狼星红染色检查肝组织。
结果
基于已被认可的小分子 GLP-1R 激动剂栀子苷的小肠转录组，我们发现辛可宁具有 GLP-1R 激动剂样作用。辛可宁与 GLP-1R 具有良好的结合亲和力。辛可宁促进葡萄糖依赖性胰岛素分泌，这种作用可以被 Exendin（9-39）显著抑制，Exendin（9-39）是一种特异性 GLP-1R 拮抗剂。此外，辛可宁可降低 C57BL/6 和 hGLP-1R 小鼠的血糖，这种作用可被 GLP-1R 敲除抑制。此外，辛可宁可降低 ob/ob-GAN NASH 小鼠的体重增加和食物摄入，呈剂量依赖性。100mg/kg 辛可宁可通过降低 ALT、ALP 和 LDH 水平显著改善肝功能。重要的是，100mg/kg 辛可宁可改善 NASH 小鼠的肝脂肪变性和纤维化。
结论
辛可宁，一种有潜力的口服小分子 GLP-1R 激动剂，可降低血糖并改善 NASH，为开发小分子 GLP-1R 激动剂提供了一种策略。
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