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

doi:10.1002/anie.201804875

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

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

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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.

Original language	English
Pages (from-to)	11608-11612
Number of pages	5
Journal	Angewandte Chemie. International Edition
Volume	57
Issue number	36
Early online date	21 Jun 2018
DOIs	https://doi.org/10.1002/anie.201804875
Publication status	Published - 3 Sept 2018

Funding

We acknowledge the Netherlands Organisation for Scientific Research for financial support (TOPPUNT, “7 ways to 7TMR modulation (7-to-7)”, 718.014.002). We thank Danny Scholten, Chris de Graaf, Shanliang Sun, and Luc Roumen for helpful discussions, Hans Custers for recording HRMS spectra, and Mounir Andaloussi for providing 4. We acknowledge the Netherlands Organisation for Scientific Research for financial support (TOPPUNT, “7 ways to 7TMR modulation (7-to-7)”, 718.014.002). We thank Danny Schol-ten, Chris de Graaf, Shanliang Sun, and Luc Roumen for helpful discussions, Hans Custers for recording HRMS spectra, and Mounir Andaloussi for providing 4.

Funders	Funder number
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	7-to-7, 718.014.002

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

azo compounds
efficacy photoswitching
G protein-coupled receptors
photochromism
photopharmacology

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10.1002/anie.201804875

anie.201804875_Photoswitching the Efficacy of a SmallMolecule Ligand for a Peptidergic GPCRFinal published version, 2.16 MBLicence: Article 25fa Dutch Copyright Act

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Gómez-Santacana, X., de Munnik, S. M., Vijayachandran, P., Da Costa Pereira, D., Bebelman, J. P. M., de Esch, I. J. P., Vischer, H. F., Wijtmans, M., & Leurs, R. (2018). Photoswitching the Efficacy of a Small-Molecule Ligand for a Peptidergic GPCR: from Antagonism to Agonism. Angewandte Chemie. International Edition, 57(36), 11608-11612. https://doi.org/10.1002/anie.201804875

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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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Gómez-Santacana, X, de Munnik, SM, Vijayachandran, P, Da Costa Pereira, D, Bebelman, JPM, de Esch, IJP , Vischer, HF , Wijtmans, M & Leurs, R 2018, 'Photoswitching the Efficacy of a Small-Molecule Ligand for a Peptidergic GPCR: from Antagonism to Agonism', Angewandte Chemie. International Edition, vol. 57, no. 36, pp. 11608-11612. https://doi.org/10.1002/anie.201804875

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AU - Vijayachandran, Prashanna

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

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UN SDGs

Keywords

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