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[摘要]：This letter provides the first pharmacological proof of principle that the sst(3) receptor mediates glucose-stimulated insulin secretion (GSIS) from pancreatic beta-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-beta-carboline (5a), with improved ion channel selectivity and mouse pharmacokinetic properties as compared to previously described tetrahydro-beta-carboline imidazole sst3 antagonists. We demonstrated that compound 5a enhances GSIS in pancreatic beta-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 sst(3) knockout mice. Thus, we have shown that antagonism of sst(3) represents a new mechanism with potential in treating type 2 diabetes mellitus. |
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