N′,2-Diphenylquinoline-4-carbohydrazide based NK3 receptor antagonists

The development and maintenance of spatial patterns and the way they affect the dynamics of populations and ecosystems is a key issue in ecology. Since each individual and each species experiences the environment on a unique range of scales, it is vital to determine the spatial scales across which organisms interact with each other and the structuring influence of their environments, which can be achieved by analyzing species’ distribution patterns. Here, the spatial variation in the distribution of <i>Scrobicularia plana</i> is described for 4 intertidal areas along the species’ distributional range. Spatial autocorrelation correlograms based on Moran’s coefficient reveal that while the Trondheim (Norway) population was randomly distributed, at Minho (Portugal), the Westerschelde, and the Wadden Sea (both in The Netherlands) populations were aggregated. Patch diameter varied from 150 to 1250 m, in Minho and Westerschelde, respectively; while in the Wadden Sea, patches of 4 to 10 km were detected. Comparisons of spatial patterns with those of other co-occurring bivalve species (<i>Abra tenuis</i>, <i>Cerastoderma edule</i>, and <i>Macoma balthica</i>) revealed that <i>S. plana</i>’s distribution was generally patchier. The distribution of <i>S. plana</i> was correlated with sediment type at Westerschelde and Trondheim, but not Minho. The observed differences in distribution patterns and their correlation with environmental factors reveal that spatial patterns of <i>S. plana</i> are site-specific rather than species-specific

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

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 (1<i>R</i>,3<i>R</i>)-3-(5-phenyl-1<i>H</i>-imidazol-2-yl)-1-(tetrahydro-2<i>H</i>-pyran-4-yl)-2,3,4,9-tetrahydro-1<i>H</i>-β-carboline (<b>5a</b>), with improved ion channel selectivity and mouse pharmacokinetic properties as compared to previously described tetrahydro-β-carboline imidazole sst3 antagonists. We demonstrated that compound <b>5a</b> 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

Diamine Derivatives as Novel Small-Molecule, Potent, and Subtype-Selective Somatostatin SST3 Receptor Agonists

A novel class of small-molecule, highly potent, and subtype-selective somatostatin SST3 agonists was discovered through modification of a SST3 antagonist. As an example, (1<i>R</i>,2<i>S</i>)-<b>9</b> demonstrated not only potent in vitro SST3 agonist activity but also in vivo SST3 agonist activity in a mouse oral glucose tolerance test (OGTT). These agonists may be useful reagents for studying the physiological roles of the SST3 receptor and may potentially be useful as therapeutic agents