Small-molecule agonists for the glucagon-like peptide 1 receptor

Knudsen, L.B. et al.
Novo Nordisk Als, Maaloev, Denmark
Proceedings of the National Academy of Sciences
Jan. 16, 2007 [PubMed]

The GLP1 peptide lowers glucose and weight in type 2 diabetes patients.

The peptide has to be injected daily.

Have identified compounds that act as both independent agonists and increases affinity of GLP1 for its receptor.

Calls type 2 diabetes and associated obesity a worldwide pandemic.

GLP1, 30 AA protein, synthesized in the small intestine.

Nauck, MA et al. and Zander, M et al. have shown clinical efficacy of GLP1 for treating diabetes.

GLP1 stimulates glucose-independent release of insulin from the pancreas and insulin, glucokinase, and glucose transporter biosynthesis.

Also act to; (i) growth, proliferation, and antiapoptosis of pancreatic beta cells and neogenesis from ductal precursor cells; (ii) glucosedependent lowering of glucagon secretion, leading to lower hepatic glucose output; (iii) inhibition of gastric acid secretion and gastric emptying, the latter causing a reduction in postprandial plasma glucose excursions; and (iv) inhibition of appetite and lowering of food intake leading to decreased body weight.

Also has neuro and cardio protective activities.

High doses of GLP1 induce nausea and it has a short half-life

Exenatide, a GLP-1 analog originally isolated from the saliva of the Gila monster, recently was approved by the Food and Drug Administration as a twice-daily treatment regimen.

Liraglutide, another peptide analog is in phase 3 clinical trials for once daily treatments.

Identified a single small molecule that was specific for GLP1R and did not displace GLP1 binding.

Compound was not antagonized by Extendin.

Compound 2 (modified version of original compound) had no effect on insulin release in islet cells from Glp1r KO mice indicated specificity.

It is possible the compound is stimulating homodimerization of the receptor to produce the increased binding affinity of GLP1.

Authors state that compound is not potent enough to be used as drug.

Paper lacks any in vivo data. Can not determine if compound would have any activity in an animal or what dose would be needed for activity in an animal. Compound can bind and activate GLP1R in a cell based assay and ex vivo experiments show the expected effect on pancreatic tissue and cells (1mM in cells and 10microM in perfused tissues).