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

Abstract

This letter provides the first pharmacological proof of principle that the sst3 receptor mediates glucose-stimulated insulin secretion (GSIS) from pancreatic β-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-β-carboline (5a), with improved ion channel selectivity and mouse pharmacokinetic properties as compared to previously described tetrahydro-β-carboline imidazole sst3 antagonists. We demonstrated that compound 5a enhances GSIS in pancreatic β-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.

Discovery of substituted (4-phenyl-1H-imidazol-2-yl)methanamine as potent somatostatin receptor 3 agonists

“…In a glucose tolerance test (GTT), a small molecule SSTR3 antagonist was shown to enhance glucose-dependent insulin secretion (GDIS) in mouse islets and reduce blood glucose excursion in wild-type mice but not in SSTR3 knock-out mice. 8 Therefore, inhibitors of SSTR3 have emerged as new potential drug therapies for type 2 diabetes mellitus. Considerable efforts have been reported on the development of non-peptidic SSTR3 antagonists.…”

Substituted oxadiazoles: a patent review (2010 – 2012)

“…The functions of somatostatin are mediated through five G-protein--coupled receptors (GPCRs) (SSTR1-SSTR5) [35]. It has been found that SSTR3 antagonists enhance glucose-dependent insulin secretion (GDIS) in mouse islets and reduce blood glucose levels during a glucose tolerance test [36]. Therefore, antagonism of SSTR3 has the potential to be a novel GDIS mechanism for the treatment of type 2 diabetes mellitus (T2DM).…”

The Discovery of MK-4256, a Potent SSTR3 Antagonist as a Potential Treatment of Type 2 Diabetes

“…The importance of SSTR3 in regulating GDIS and glucose homeostasis was further supported by the fact that a selective SSTR3 antagonist enhanced GDIS in mouse islets and reduced blood glucose levels during a glucose tolerance test (GTT) (Figure 1). 15 The glucose lowering was not observed with SSTR3 knockout mice. 15 Mechanistically, SSTR3 signals primarily through Gα i -mediated inhibition of cAMP production.…”

“…15 The glucose lowering was not observed with SSTR3 knockout mice. 15 Mechanistically, SSTR3 signals primarily through Gα i -mediated inhibition of cAMP production. Therefore, antagonists of SSTR3 most likely enhance GDIS by increasing intracellular cAMP levels in pancreatic βcells, a mechanism that is similar to GLP-1 analogues, which is proven to be a glucose-dependent mechanism.…”