Small-molecule agonists for the glucagon-like peptide 1 receptor
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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.
Original language | English |
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Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 104 |
Issue number | 3 |
Pages (from-to) | 937-42 |
Number of pages | 6 |
ISSN | 0027-8424 |
DOIs | |
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
Research areas
ID: 132050443