Stimulation of Glucose-Dependent Insulin Secretion by a Potent, Selective sst3 Antagonist

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• 作者：Alexander Pasternak ; Zhe Feng ; Reynalda de Jesus ; Zhixiong Ye ; Shuwen He ; Peter Dobbelaar ; Scott A. Bradley ; Gary G. Chicchi ; Kwei-Lan Tsao ; Dorina Trusca ; George J. Eiermann ; Cai Li ; Yue Feng ; Margaret Wu ; Qing Shao ; Bei B. Zhang ; Ravi Nargund ; Sander G. Mills ; Andrew D. Howard ; Lihu Yang ; Yun-Ping Zhou
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：April 12, 2012
• 年：2012
• 卷：3
• 期：4
• 页码：289-293
• 全文大小：329K
• 年卷期：v.3,no.4(April 12, 2012)
• ISSN：1948-5875

文摘

This letter provides the first pharmacological proof of principle that the sst₃ receptor mediates glucose-stimulated insulin secretion (GSIS) from pancreatic 尾-cells. To enable these studies, we identified the selective sst₃ antagonist (1R,3R)-3-(5-phenyl-1H-imidazol-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-尾-carboline (5a), with improved ion channel selectivity and mouse pharmacokinetic properties as compared to previously described tetrahydro-尾-carboline imidazole sst3 antagonists. We demonstrated that compound 5a enhances GSIS in pancreatic 尾-cells and blocks glucose excursion induced by dextrose challenge in ipGTT and OGTT models in mice. Finally, we provided strong evidence that these effects are mechanism-based in an ipGTT study, showing reduction of glucose excursion in wild-type but not sst₃ knockout mice. Thus, we have shown that antagonism of sst₃ represents a new mechanism with potential in treating type 2 diabetes mellitus.

Keywords:

somatostatin; type 2 diabetes; sst₃; glucose-stimulated insulin secretion