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

Xavier Gómez-Santacana, Sabrina M. de Munnik, Prashanna Vijayachandran, Daniel Da Costa Pereira, Jan Paul M. Bebelman, Iwan J.P. de Esch, Henry F. Vischer, Maikel Wijtmans, Rob Leurs

Research output: Contribution to JournalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)11608-11612
Number of pages5
JournalAngewandte Chemie - International Edition
Volume57
Issue number36
Early online date21 Jun 2018
DOIs
Publication statusPublished - 3 Sep 2018

Fingerprint

Ligands
Molecules
Chemical activation
Electrophysiology
Proteins
Azobenzene
Chemokine Receptors
GTP-Binding Proteins
Assays
Electrons
Experiments
azobenzene

Keywords

  • azo compounds
  • efficacy photoswitching
  • G protein-coupled receptors
  • photochromism
  • photopharmacology

Cite this

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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.",
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Photoswitching the Efficacy of a Small-Molecule Ligand for a Peptidergic GPCR : from Antagonism to Agonism. / 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.

In: Angewandte Chemie - International Edition, Vol. 57, No. 36, 03.09.2018, p. 11608-11612.

Research output: Contribution to JournalArticleAcademicpeer-review

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