| Literature DB >> 17213325 |
Lotte Bjerre Knudsen1, Dan Kiel, Min Teng, Carsten Behrens, Dilip Bhumralkar, János T Kodra, Jens J 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, John May, Jesper Lau.
Abstract
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.Entities:
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Year: 2007 PMID： 17213325 PMCID： PMC1783418 DOI： 10.1073/pnas.0605701104
Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 11.205