Small-molecule agonists for the glucagon-like peptide 1 receptor
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Small-molecule agonists for the glucagon-like peptide 1 receptor. / Knudsen, Lotte Bjerre; Kiel, Dan; Teng, Min; Behrens, Carsten; Bhumralkar, Dilip; Kodra, János T; Holst, Jens Juul; Jeppesen, Claus B; Johnson, Michael D; de Jong, Johannes Cornelis; Jorgensen, Anker Steen; Kercher, Tim; Kostrowicki, Jarek; Madsen, Peter; Olesen, Preben H; Petersen, Jacob S; Poulsen, Fritz; Sidelmann, Ulla G; Sturis, Jeppe; Truesdale, Larry; May, John; Lau, Jesper.
I: Proceedings of the National Academy of Sciences of the United States of America, Bind 104, Nr. 3, 16.01.2007, s. 937-42.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Small-molecule agonists for the glucagon-like peptide 1 receptor
AU - Knudsen, Lotte Bjerre
AU - Kiel, Dan
AU - Teng, Min
AU - Behrens, Carsten
AU - Bhumralkar, Dilip
AU - Kodra, János T
AU - Holst, Jens Juul
AU - Jeppesen, Claus B
AU - Johnson, Michael D
AU - de Jong, Johannes Cornelis
AU - Jorgensen, Anker Steen
AU - Kercher, Tim
AU - Kostrowicki, Jarek
AU - Madsen, Peter
AU - Olesen, Preben H
AU - Petersen, Jacob S
AU - Poulsen, Fritz
AU - Sidelmann, Ulla G
AU - Sturis, Jeppe
AU - Truesdale, Larry
AU - May, John
AU - Lau, Jesper
PY - 2007/1/16
Y1 - 2007/1/16
N2 - 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.
AB - 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.
KW - Animals
KW - Cells, Cultured
KW - Cricetinae
KW - Drug Evaluation, Preclinical
KW - Glucagon-Like Peptides
KW - Humans
KW - Insulin
KW - Mice
KW - Mice, Knockout
KW - Molecular Structure
KW - Pancreas
KW - Perfusion
KW - Quinoxalines
KW - Receptors, Glucagon
KW - Sulfones
KW - Thiadiazoles
U2 - 10.1073/pnas.0605701104
DO - 10.1073/pnas.0605701104
M3 - Journal article
C2 - 17213325
VL - 104
SP - 937
EP - 942
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 3
ER -
ID: 132050443