Discovery and characterization of novel small-molecule agonists of G protein-coupled receptor 119
文献类型：期刊论文
| 作者 | Zhang, Shu-yong1; Li, Jing2 ; Xie, Xin1,2
|
| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 2014-04 |
| 卷号 | 35期号:4页码:540-548 |
| 关键词 | GPCR GPR119 PSN632408 AR231453 high-throughput screening cAMP Ca2+ beta-cell insulin obesity type 2 diabetes mellitus |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/aps.2014.8 |
| 文献子类 | Article |
| 英文摘要 | Aim: GPR119 is a G protein-coupled receptor (GPCR) that is highly expressed in pancreatic beta-cells and intestinal L-cells and facilitates glucose-stimulated insulin secretion (GSIS). GPR119 may represent a novel target for the treatment of metabolic disorders. Here, we sought to identify novel small-molecule GPR119 agonists. Methods: A cell-based high-throughput screening assay was established using HEK293 cells stably expressing GPR119 and pCRE-luc reporter plasmid (HEK293/GPR119/pCRE-luc). A compound library composed of 1440 compounds was screened. Mouse beta-cell line MIN-6 and isolated mouse islets were used to evaluate the effects of candidate compounds on GSIS in vitro. Results: Three compounds with novel structures (ZSY-04, -06, and -13) were found to activate GPR119-mediated signaling and to induce GPR119 desensitization. The EC50 values of ZSY-04, -06, and -13 in stimulating intracellular cAMP accumulation in HEK293/GPR119 cells were 2.758, 3.046, and 0.778 mu mol/L, respectively. Furthermore, all three compounds displayed high selectivity for GPR119, and did not activate other 9 GPCRs tested. Moreover, all three compounds significantly increased GSIS in both MIN-6 mouse beta-cells and isolated mouse islets at concentration of 10 mu mol/L. Conclusion: Three novel small-molecule GPR119 agonists (ZSY-04, -06, and -13) with high receptor selectivity and capacity to induce GSIS in vitro were discovered. These compounds are potential candidates to be structurally optimized into drugs for the treatment of type 2 diabetes. |
| WOS关键词 | GLUCAGON-LIKE PEPTIDE-1 ; STIMULATED INSULIN-SECRETION ; PANCREATIC BETA-CELL ; GPR119 AGONIST ; GLYCEMIC CONTROL ; GLUCOSE ; G-PROTEIN-COUPLED-RECEPTOR-119 ; OLEOYLETHANOLAMIDE ; IDENTIFICATION ; AS1535907 |
| 资助项目 | Ministry of Science and Technology of China[2013ZX09507001] ; Ministry of Science and Technology of China[2012ZX09301001-005] ; Ministry of Science and Technology of China[2014CB541906] ; National Natural Science Foundation of China[81202341] ; Shanghai Commission of Science and Technology[11ZR1408000] ; Shanghai Commission of Science and Technology[12XD1402100] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| CSCD记录号 | CSCD:5106726 |
| WOS记录号 | WOS:000334417500012 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277138]  |
| 专题 | 国家新药筛选中心 |
| 通讯作者 | Xie, Xin |
| 作者单位 | 1.Tongji Univ, Sch Life Sci & Technol, Shanghai Key Lab Signaling & Dis Res, Lab Receptor Based Biomed, Shanghai 200092, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Key Lab Receptor Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhang, Shu-yong,Li, Jing,Xie, Xin. Discovery and characterization of novel small-molecule agonists of G protein-coupled receptor 119[J]. ACTA PHARMACOLOGICA SINICA,2014,35(4):540-548. |
| APA | Zhang, Shu-yong,Li, Jing,&Xie, Xin.(2014).Discovery and characterization of novel small-molecule agonists of G protein-coupled receptor 119.ACTA PHARMACOLOGICA SINICA,35(4),540-548. |
| MLA | Zhang, Shu-yong,et al."Discovery and characterization of novel small-molecule agonists of G protein-coupled receptor 119".ACTA PHARMACOLOGICA SINICA 35.4(2014):540-548. |
入库方式： OAI收割
来源：上海药物研究所
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