Photoswitching the Efficacy of a Small‐Molecule Ligand for a Peptidergic GPCR: from Antagonism to Agonism

For optical control of GPCR function, we set out to develop small‐molecule ligands with photoswitchable efficacy in which both configurations bind the target protein but exert distinct pharmacological effects, that is, stimulate or antagonize GPCR activation. Our design was based on a previously ide...

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Published in:Angewandte Chemie International Edition 2018-09, Vol.57 (36), p.11608-11612
Main Authors: Gómez‐Santacana, Xavier, de Munnik, Sabrina M., Vijayachandran, Prashanna, Da Costa Pereira, Daniel, Bebelman, Jan Paul M., de Esch, Iwan J. P., Vischer, Henry F., Wijtmans, Maikel, Leurs, Rob
Format: Article
Language:English
Subjects:
Activation
Aromatic compounds
azo compounds
CXCR3 protein
Effectiveness
efficacy photoswitching
Electrophysiology
G protein-coupled receptors
Ligands
Optical control
Pharmacology
photochromism
photopharmacology
Proteins
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Summary:For optical control of GPCR function, we set out to develop small‐molecule ligands with photoswitchable efficacy in which both configurations bind the target protein but exert distinct pharmacological effects, that is, stimulate or antagonize GPCR activation. Our design was based on a previously identified efficacy hotspot for the peptidergic chemokine receptor CXCR3 and resulted in the synthesis and characterization of five new azobenzene‐containing CXCR3 ligands. G protein activation assays and real‐time electrophysiology experiments demonstrated photoswitching from antagonism to partial agonism and even to full agonism (compound VUF16216). SAR evaluation suggests that the size and electron‐donating properties of the substituents on the inner aromatic ring are important for the efficacy photoswitching. These compounds are the first GPCR azo ligands with a nearly full efficacy photoswitch and may become valuable pharmacological tools for the optical control of peptidergic GPCR signaling. Spatiotemporal optical control of GPCRs was obtained by developing efficacy photoswitchable ligands for a peptidergic GPCR. G protein activation assays and real‐time electrophysiology experiments validated a photoswitching from antagonism to partial agonism and to full agonism. VUF16216 is the first GPCR azo‐ligand with almost full efficacy photoswitch and it may become a valuable tool for the optical control of GPCR activity.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201804875