PT  - JOURNAL ARTICLE
AU  - Denise Wootten
AU  - Emilia E Savage
AU  - Francis S Willard
AU  - Ana B Bueno
AU  - Kyle W Sloop
AU  - Arthur Christopoulos
AU  - Patrick Sexton
TI  - Differential Activation and Modulation of the Glucagon-like Peptide-1 Receptor by Small Molecule Ligands
AID  - 10.1124/mol.112.084525
DP  - 2013 Jan 24
TA  - Molecular Pharmacology
PG  - mol.112.084525
4099  - http://molpharm.aspetjournals.org/content/early/2013/01/24/mol.112.084525.short
4100  - http://molpharm.aspetjournals.org/content/early/2013/01/24/mol.112.084525.full
AB  - 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 signalling 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 signalling pathways that they activate. Furthermore, allosteric, small molecule ligands were able to induce bias in signalling 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 signalling profile. We highlight the need to profile compounds across multiple signalling 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 physiological responses, profiling of small molecules in this manner may lead to a better understanding of the physiological consequences of biased signalling at this receptor. This could enable the design and development of improved therapeutics that have the ability to fine-tune receptor signalling leading to beneficial therapeutic outcomes while reducing side effect profiles.