+44 (0)1509 263171
Please use this identifier to cite or link to this item:
|Title: ||Comparative effects of the endogenous agonist glucagon-like peptide-1 (GLP-1)-(7-36) amide and the small-molecule ago-allosteric agent 'compound 2' at the GLP-1 receptor|
|Authors: ||Coopman, Karen|
Bradley, Sophie J.
Wilkinson, Graeme F.
Willars, Gary B.
|Issue Date: ||2010|
|Publisher: ||© American Society for Pharmacology and Experimental Therapeutics|
|Citation: ||COOPMAN, K. ... et al, 2010. Comparative effects of the endogenous agonist glucagon-like peptide-1 (GLP-1)-(7-36) amide and the small-molecule ago-allosteric agent 'compound 2' at the GLP-1 receptor. The Journal of Pharmacology and Experimental Therapeutics, 334 (3), pp. 795-808.|
|Abstract: ||Glucagon-like peptide-1 (GLP-1) mediates antidiabetogenic effects through the GLP-1 receptor (GLP-1R), which is targeted for the treatment of type 2 diabetes. Small-molecule GLP-1R agonists have been sought due to difficulties with peptide therapeutics. Recently, 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (compound 2) has been described as a GLP-1R allosteric modulator and agonist. Using human embryonic kidney-293 cells expressing human GLP-1Rs, we extended this work to consider the impact of compound 2 on G protein activation, Ca2+ signaling and receptor internalization and particularly to compare compound 2 and GLP-1 across a range of functional assays in intact cells. GLP-1 and compound 2 activated Gαs in cell membranes and increased cellular cAMP in intact cells, with compound 2 being a partial and almost full agonist, respectively. GLP-1 increased intracellular [Ca2+] by release from intracellular stores, which was mimicked by compound 2, with slower kinetics. In either intact cells or membranes, the orthosteric antagonist exendin-(9-39), inhibited GLP-1 cAMP generation but increased the efficacy of compound 2. GLP-1 internalized enhanced green fluorescent protein-tagged GLP-1Rs, but the speed and magnitude evoked by compound 2 were less. Exendin-(9-39) inhibited internalization by GLP-1 and also surprisingly that by compound 2. Compound 2 displays GLP-1R agonism consistent with action at an allosteric site, although an orthosteric antagonist increased its efficacy on cAMP and blocked compound 2-mediated receptor internalization. Full assessment of the properties of compound 2 was potentially hampered by damaging effects that were particularly manifest in either longer term assays with intact cells or in acute assays with membranes.|
|Description: ||This item is closed access|
|Version: ||Closed access|
|Publisher Link: ||http://dx.doi.org/10.1124/jpet.110.166009|
|Appears in Collections:||Closed Access (Chemical Engineering)|
Files associated with this item:
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.