Document Detail

Differential activation and modulation of the glucagon-like peptide-1 receptor by small molecule ligands.
MedLine Citation:
PMID:  23348499     Owner:  NLM     Status:  MEDLINE    
The glucagon-like peptide-1 receptor (GLP-1R) is a major therapeutic target for the treatment of type 2 diabetes due to its role in glucose homeostasis. Despite the availability of peptide-based GLP-1R drugs for treatment of this disease, there is great interest in developing small molecules that can be administered orally. The GLP-1R system is complex, with multiple endogenous and clinically used peptide ligands that exhibit different signaling biases at this receptor. This study revealed that small molecule ligands acting at this receptor are differentially biased to peptide ligands and also from each other with respect to the signaling pathways that they activate. Furthermore, allosteric small molecule ligands were also able to induce bias in signaling mediated by orthosteric ligands. This was dependent on both the orthosteric and allosteric ligand as no two allosteric-orthosteric ligand pairs could induce the same signaling profile. We highlight the need to profile compounds across multiple signaling pathways and in combination with multiple orthosteric ligands in systems such as the GLP-1R where more than one endogenous ligand exists. In the context of pleiotropical coupling of receptors and the interplay of multiple pathways leading to physiologic responses, profiling of small molecules in this manner may lead to a better understanding of the physiologic consequences of biased signaling at this receptor. This could enable the design and development of improved therapeutics that have the ability to fine-tune receptor signaling, leading to beneficial therapeutic outcomes while reducing side effect profiles.
Denise Wootten; Emilia E Savage; Francis S Willard; Ana B Bueno; Kyle W Sloop; Arthur Christopoulos; Patrick M Sexton
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-24
Journal Detail:
Title:  Molecular pharmacology     Volume:  83     ISSN:  1521-0111     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-20     Completed Date:  2013-05-14     Revised Date:  2013-08-08    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  822-34     Citation Subset:  IM    
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia.
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MeSH Terms
CHO Cells
Cyclobutanes / metabolism*,  pharmacology
Receptors, Glucagon / agonists*,  metabolism*
Signal Transduction / drug effects,  physiology
Reg. No./Substance:
0/Boc5 compound; 0/Cyclobutanes; 0/Ligands; 0/Receptors, Glucagon; 0/glucagon-like peptide-1 receptor
Erratum In:
Mol Pharmacol. 2013 Jul;84(1):170

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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