Small-molecule agonists for the glucagon-like peptide 1 receptor
Research output: Contribution to journal › Journal article › Research › peer-review
Lotte Bjerre Knudsen, Dan Kiel, Min Teng, Carsten Behrens, Dilip Bhumralkar, János T Kodra, Jens Juul Holst, Claus B Jeppesen, Michael D Johnson, Johannes Cornelis de Jong, Anker Steen Jorgensen, Tim Kercher, Jarek Kostrowicki, Peter Madsen, Preben H Olesen, Jacob S Petersen, Fritz Poulsen, Ulla G Sidelmann, Jeppe Sturis, Larry Truesdale & 2 others
The peptide hormone glucagon-like peptide (GLP)-1 has important actions resulting in glucose lowering along with weight loss in patients with type 2 diabetes. As a peptide hormone, GLP-1 has to be administered by injection. Only a few small-molecule agonists to peptide hormone receptors have been described and none in the B family of the G protein coupled receptors to which the GLP-1 receptor belongs. We have discovered a series of small molecules known as ago-allosteric modulators selective for the human GLP-1 receptor. These compounds act as both allosteric activators of the receptor and independent agonists. Potency of GLP-1 was not changed by the allosteric agonists, but affinity of GLP-1 for the receptor was increased. The most potent compound identified stimulates glucose-dependent insulin release from normal mouse islets but, importantly, not from GLP-1 receptor knockout mice. Also, the compound stimulates insulin release from perfused rat pancreas in a manner additive with GLP-1 itself. These compounds may lead to the identification or design of orally active GLP-1 agonists.
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Number of pages||6|
|Publication status||Published - 16 Jan 2007|
- Animals, Cells, Cultured, Cricetinae, Drug Evaluation, Preclinical, Glucagon-Like Peptides, Humans, Insulin, Mice, Mice, Knockout, Molecular Structure, Pancreas, Perfusion, Quinoxalines, Receptors, Glucagon, Sulfones, Thiadiazoles