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Allosteric regulation promises to open up new therapeutic avenues by increasing drug specificity at G-protein-coupled receptors (GPCRs). However, drug discovery efforts are at present hampered by an inability to precisely control the allosteric site. Herein, we describe the design, synthesis, and testing of PhotoETP, a light-activated positive allosteric modulator of the glucagon-like peptide-1 receptor (GLP-1R), a class B GPCR involved in the maintenance of glucose homeostasis in humans. PhotoETP potentiates Ca(2+) , cAMP, and insulin responses to glucagon-like peptide-1 and its metabolites following illumination of cells with blue light. PhotoETP thus provides a blueprint for the production of small-molecule class B GPCR allosteric photoswitches, and may represent a useful tool for understanding positive cooperativity at the GLP-1R.

Original publication

DOI

10.1002/anie.201600957

Type

Journal article

Journal

Angew Chem Int Ed Engl

Publication Date

04/05/2016

Volume

55

Pages

5865 - 5868

Keywords

GLP-1 receptor, allosteric regulation, beta cells, photopharmacology, type 2 diabetes, Allosteric Regulation, Aniline Compounds, Animals, Azo Compounds, CHO Cells, Calcium, Cell Survival, Cricetinae, Cricetulus, Cyclic AMP, Glucagon-Like Peptide-1 Receptor, Humans, Insulin, Isomerism, Light, Pyrimidines, Ultraviolet Rays