ol3anovellowabsorbedtgr5agonistwithreducedsideeffectsloweredbloodglucoseviadualactionsontgr5activationanddpp4inhibition
文献类型：期刊论文
| 作者 | Ma Shanyao; Ning Mengmeng ; Zou Qingan; Feng Ying; Ye Yangliang; Shen Jianhua; Leng Ying
|
| 刊名 | actapharmacologicasinica
 |
| 出版日期 | 2016 |
| 卷号 | 000期号:010页码:1359 |
| 关键词 | OL3 MN6 linagliptin TGR5 agonist DPP4 inhibitor GLP-1 low-absorbed gallbladder filling type 2 diabetes mellitus |
| ISSN号 | 1671-4083 |
| 英文摘要 | Aim： TGR5 agonists stimulate intestinal glucagon-like peptide-1 （GLP-1） release, but systemic exposure causes unwanted side effects, such as gallbladder filling. In the present study, linagliptin, a DPP-4 inhibitor with a large molecular weight and polarity, and MN6, a previously described TGR5 agonist, were linked to produce OL3, a novel low-absorbed TGR5 agonist with reduced side-effects and dua function in lowering blood glucose by activation of TGR5 and inhibition of DPP-4. Methods： TGR5 activation was assayed in HEK293 cells stably expressing human or mouse TGR5 and a CRE-driven luciferase gene. DPP-4 inhibition was assessed based on the rate of hydrolysis of a surrogate substrate. GLP-1 secretion was measured in human enteroendocrine NCI-H716 cells. OL3 permeability was tested in Caco-2 cells. Acute glucose-lowering effects of OL3 were evaluated in tCR and diabetic ob/ob mice. Results： OL3 activated human and mouse TGR5 with an ECho of 86.24 and 17.36 nmol/L, respectively, and stimulated GLP-1 secretion in human enteroendocrine NCI-H716 cells （3-30 pmol/L）. OL3 inhibited human and mouse DPP-4 with IC50 values of 18.44 and 69.98 pmol/L, respectively. Low permeability of OL3 was observed in Caco-2 cells. In ICR mice treated orally with OL3 （150 mg/kg）, the serum OL3 concentration was 101.10 ng/mL at I h, and decreased to 13.38 ng/mL at 5.5 h post dose, confirming the low absorption of OL3 in vivo. In ICR mice and ob/ob mice, oral administration of OL3 significantly lowered the blood glucose levels, which was a synergic effect of activating TGR5 that stimulated GLP-1 secretion in the intestine and inhibiting DPP-4 that cleaved GLP-1 in the plasma. In ICR mice, oral administration of OL3 did not cause gallbladder filling. Conclusion： OL3 is a low-absorbed TGR5 agonist that lowers blood glucose without inducing gallbladder filling. This study presents a new strategy in the development of potent TGR5 agonists in treating type 2 diabetes, which target to the intestine to avoid systemic side effects. |
| 语种 | 英语 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/287790]  |
| 专题 | 中国科学院上海药物研究所 |
| 作者单位 | 中国科学院上海药物研究所 |
| 推荐引用方式 GB/T 7714 | Ma Shanyao,Ning Mengmeng,Zou Qingan,et al. ol3anovellowabsorbedtgr5agonistwithreducedsideeffectsloweredbloodglucoseviadualactionsontgr5activationanddpp4inhibition[J]. actapharmacologicasinica,2016,000(010):1359. |
| APA | Ma Shanyao.,Ning Mengmeng.,Zou Qingan.,Feng Ying.,Ye Yangliang.,...&Leng Ying.(2016).ol3anovellowabsorbedtgr5agonistwithreducedsideeffectsloweredbloodglucoseviadualactionsontgr5activationanddpp4inhibition.actapharmacologicasinica,000(010),1359. |
| MLA | Ma Shanyao,et al."ol3anovellowabsorbedtgr5agonistwithreducedsideeffectsloweredbloodglucoseviadualactionsontgr5activationanddpp4inhibition".actapharmacologicasinica 000.010(2016):1359. |
入库方式： OAI收割
来源：上海药物研究所
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