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保护胰腺小岛免受氧化细胞死亡,由外周活性吗啡,增加药物安全性

Okka Scholz¹, Elena Huß¹, Silke Otter¹

¹Institute of Metabolic Physiology, Heinrich Heine University, D-40225 Düsseldorf, Germany; Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, D-40225 Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, Neuherberg, D-85764 Neuherberg, Germany.

Molecular metabolism

|July 14, 2023

概括

研究人员开发了一种新的德克斯特罗梅索芬 (DXM) 衍生物来治疗2型糖尿病. 这种修改后的化合物改善了葡萄糖耐受性,并保护了胰腺细胞,没有中枢神经系统的副作用或心脏通道相互作用.

科学领域:

药理学药理学是指药理学的学科.
内分泌学在内分泌学.
药用化学医学化学

背景情况:

德克斯甲 (DXM) 通过增强葡萄糖耐受性和保护胰腺小岛,显示出抗糖尿病潜力.
DXM的限制包括中枢神经系统的副作用和娱乐性滥用潜力.
之前的DXM衍生物旨在减少血脑屏障 (BBB) 透,但显示出与hERG和μ-阿片类受体 (MOR) 的非目标结合.

研究的目的:

设计和合成一种具有减少hERG和MOR结合的新型DXM衍生物.
保持或改善DXM的抗糖尿病特性,包括耐葡萄糖性和小岛细胞保护.
为了确保该化合物可以口服,BBB无,并具有良好的药物安全性.

主要方法:

一种新型的吗啡衍生物的合成.
在体外测定hERG和MOR结合.
使用脑液收集和行为测试评估BBB透性的评估.
通过葡萄糖耐受性测试和胰岛素分泌量测试来评估抗糖尿病作用.
使用光显微镜和流细胞计进行小岛细胞保护试验.

主要成果:

与之前的化合物相比,合成了一种优化,口服可用的,BBB无透的DXM衍生物,与hERG和MOR结合减少.
这种新化合物显著增强了老鼠和人类小岛的葡萄糖刺激胰岛素分泌 (GSIS).
在小鼠中观察到改善的葡萄糖耐受性和保护胰腺小岛免受氧化应激诱导的细胞死亡.
该衍生物放大了蒂尔泽帕提德对GSIS和小岛细胞活力的有益作用.

结论:

一种新的吗啡衍生物成功设计和合成.
该化合物具有BBB无性,降低葡萄糖,并保护小岛细胞.
尽管该衍生品具有摩尔菲南和伊米达结构,但其药物安全性很好,为2型糖尿病提供了有前途的治疗候选者.

关键词:

血脑屏障血脑屏障血脑屏障血脑屏障德克斯特罗米多芬 (Dextromethorphan) 是一种含有甲基的药物.糖尿病是一种糖尿病.药物发现药物发现胰腺小岛细胞保护胰腺小岛是一个小岛.

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