Abstract
The glucagon-like peptide-1 receptor (GLP-1R) is an important physiologic regulator of insulin secretion and a major therapeutic target for diabetes mellitus. GLP-1 (7-36) amide (active form of GLP-1) is truncated to GLP-1 (9-36) amide, which has been described as a weak agonist of GLP-1R and the major form of GLP-1 in the circulation. New classes of positive allosteric modulators (PAMs) for GLP-1R may offer improved therapeutic profiles. To identify these new classes, we developed novel and robust primary and secondary high-throughput screening (HTS) systems in which PAMs were identified to enhance the GLP-1R signaling induced by GLP-1 (9-36) amide. Screening enabled identification of two compounds, HIT-465 and HIT-736, which possessed new patterns of modulation of GLP-1R. We investigated the ability of these compounds to modify GLP-1R signaling enhanced GLP-1 (9-36) amide- and/or GLP-1 (7-36) amide-mediated cyclic adenosine monophosphate (cAMP) accumulation. These compounds also had unique profiles with regard to allosteric modulation of multiple downstream signaling (PathHunter β-arrestin signaling, PathHunter internalization signaling, microscopy-based internalization assay). We found allosteric modulation patterns to be ob...Continue Reading
References
Apr 1, 1994·Diabetes·C OrskovJ J Holst
Dec 30, 1996·European Journal of Pharmacology·L B Knudsen, L Pridal
Aug 22, 1997·The Journal of Biological Chemistry·C Montrose-RafizadehJ Eng
Jan 11, 2007·Proceedings of the National Academy of Sciences of the United States of America·Lotte Bjerre KnudsenJesper Lau
Feb 20, 2007·Pharmacology & Therapeutics·Máire E Doyle, Josephine M Egan
May 15, 2007·Gastroenterology·Laurie L Baggio, Daniel J Drucker
Oct 12, 2007·Physiological Reviews·Jens Juul Holst
May 29, 2010·The Journal of Pharmacology and Experimental Therapeutics·Karen CoopmanGary B Willars
Jun 16, 2010·Molecular Pharmacology·Cassandra KoolePatrick M Sexton
Feb 24, 2011·Biochemistry·Michael R WoodCraig W Lindsley
May 28, 2011·Molecular Pharmacology·Cassandra KoolePatrick M Sexton
Dec 8, 2011·The Journal of Biological Chemistry·Cassandra KoolePatrick M Sexton
Jun 6, 2012·Experimental Diabetes Research·Francis S Willard, Kyle W Sloop
Oct 24, 2012·Proceedings of the National Academy of Sciences of the United States of America·Kaleeckal G HarikumarPatrick M Sexton
Jan 30, 2013·Biochemical Society Transactions·Cassandra KoolePatrick M Sexton
May 9, 2013·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Heather EngAmit S Kalgutkar
Feb 15, 2014·Journal of Biomolecular Screening·Lindsey C MorrisKevin D Niswender
May 23, 2014·Frontiers in Endocrinology·Etienne KhouryStéphane A Laporte
Sep 17, 2014·Frontiers in Endocrinology·Jonathan JanssensStuart Maudsley
Citations
May 20, 2016·Expert Opinion on Therapeutic Patents·Eun Ji ParkDong Hee Na
Dec 2, 2019·Journal of Endocrinological Investigation·W WangY Huang
Aug 5, 2020·SLAS Discovery·Daniela G DenglerEduard A Sergienko
Mar 16, 2016·The Journal of Biological Chemistry·Ana B BuenoKyle W Sloop
Mar 17, 2021·British Journal of Pharmacology·Faisal Malik, Zhijun Li