Photoswitching the Efficacy of a Small‐Molecule Ligand for a Peptidergic GPCR: from Antagonism to Agonism. Issue 36 (6th August 2018)

• Record Type: Journal Article
• 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
• Is Part Of: Angewandte Chemie international edition. Volume 57:Issue 36(2018)
• Page Start: 11608
• Page End: 11612
• Publication Date: 2018-08-06
• Subjects: azo compounds -- efficacy photoswitching -- G protein-coupled receptors -- photochromism -- photopharmacology; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201804875
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: 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. Abstract : 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.