Visible-Light Photoswitchable Benzimidazole Azo-Arenes as beta-Arrestin2-Biased Selective Cannabinoid 2 Receptor Agonists

Sophie A M Steinmueller; Julia Fender; Marie H Deventer; Anna Tutov; Kristina Lorenz; Christophe P Stove; James Hislop; Michael Decker

doi:10.1002/anie.202306176

Visible-Light Photoswitchable Benzimidazole Azo-Arenes as beta-Arrestin2-Biased Selective Cannabinoid 2 Receptor Agonists

Sophie A M Steinmueller, Julia Fender, Marie H Deventer, Anna Tutov, Kristina Lorenz, Christophe P Stove, James Hislop, Michael Decker^* (Corresponding Author)

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

5 Citations (Scopus)

Abstract

The cannabinoid 2 receptor (CB2R) has high therapeutic potential for multiple pathogenic processes, such as neuroinflammation. Pathway-selective ligands are needed to overcome the lack of clinical success and to elucidate correlations between pathways and their respective therapeutic effects. Herein, we report the design and synthesis of a photoswitchable scaffold based on the privileged structure of benzimidazole and its application as a functionally selective CB2R "efficacy-switch". Benzimidazole azo-arenes offer huge potential for the broad extension of photopharmacology to a wide range of optically addressable biological targets. We used this scaffold to develop compound 10d, a "trans-on" agonist, which serves as a molecular probe to study the β-arrestin2 (βarr2) pathway at CB2R. βArr2 bias was observed in CB2R internalization and ßarr2 recruitment, while no activation occurred when looking at Gα16 or mini-Gαi. Overall, compound 10d is the first light-dependent functionally selective agonist to investigate the complex mechanisms of CB2R-βarr2 dependent endocytosis.

Original language	English
Article number	e202306176
Number of pages	11
Journal	Angewandte Chemie International Edition
Volume	62
Issue number	49
Early online date	13 Jul 2023
DOIs	https://doi.org/10.1002/anie.202306176
Publication status	Published - 4 Dec 2023

Bibliographical note

Acknowledgements
The authors would like to acknowledge Dr. Andrea Holme for excellent technical support and the Iain Fraser Cytometry Centre (University of Aberdeen) for providing access to their equipment. The authors would like to thank Dr. Matthias Scheiner for his contributions towards the development of the calcium mobilization assay and Dr. Valérie Jahns for her efforts towards faster automated analysis of the obtained results. Nick Verhavert is acknowledged for his assistance with the NanoBiT® assay. Diego Rodriguez-Soacha is acknowledged for establishing the rCB1R radioligand binding assay in our laboratory. Special thanks to Dr. Rangan Maitra and RTI International for providing the G16
coupled hCB1 and hCB2 CHO-K1 cell lines. The authors thank Nadine Yurdagül-Hemmrich and Annette Hannawacker for excellent technical support. This project was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft under DFG DE1546/10-1). J. N. Hislop’s financing support was given by NHS Grampian. The research visit of S. A. M. Steinmüller in Dr. Hislop’s laboratory was funded by the Elite Network of Bavaria (grant N° K-BM-2013-247). J. Fender and A. Tutov were supported by the International
Doctoral Program “Receptor Dynamics” funded within the framework of the Elite Network of Bavaria (grant N° K-BM-2013- 247). M. H. Deventer was funded by the Research FoundationFlanders (FWO; grant 1S54521N).

Data Availability Statement

The data that support the findings of this study are available in the Supporting Information of this article.

Keywords

benzimidazoles
G protein-coupled receptor
optical control
photopharmacology
biased ligand

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Steinmuller_etal_ACIE_Visible_Light_Photoswitchable_VoR
© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes https://creativecommons.org/licenses/by-nc/4.0/
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Cite this

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title = "Visible-Light Photoswitchable Benzimidazole Azo-Arenes as beta-Arrestin2-Biased Selective Cannabinoid 2 Receptor Agonists",

abstract = "The cannabinoid 2 receptor (CB2R) has high therapeutic potential for multiple pathogenic processes, such as neuroinflammation. Pathway-selective ligands are needed to overcome the lack of clinical success and to elucidate correlations between pathways and their respective therapeutic effects. Herein, we report the design and synthesis of a photoswitchable scaffold based on the privileged structure of benzimidazole and its application as a functionally selective CB2R {"}efficacy-switch{"}. Benzimidazole azo-arenes offer huge potential for the broad extension of photopharmacology to a wide range of optically addressable biological targets. We used this scaffold to develop compound 10d, a {"}trans-on{"} agonist, which serves as a molecular probe to study the β-arrestin2 (βarr2) pathway at CB2R. βArr2 bias was observed in CB2R internalization and {\ss}arr2 recruitment, while no activation occurred when looking at Gα16 or mini-Gαi. Overall, compound 10d is the first light-dependent functionally selective agonist to investigate the complex mechanisms of CB2R-βarr2 dependent endocytosis.",

keywords = "benzimidazoles, G protein-coupled receptor, optical control, photopharmacology, biased ligand",

author = "Steinmueller, {Sophie A M} and Julia Fender and Deventer, {Marie H} and Anna Tutov and Kristina Lorenz and Stove, {Christophe P} and James Hislop and Michael Decker",

note = "Acknowledgements The authors would like to acknowledge Dr. Andrea Holme for excellent technical support and the Iain Fraser Cytometry Centre (University of Aberdeen) for providing access to their equipment. The authors would like to thank Dr. Matthias Scheiner for his contributions towards the development of the calcium mobilization assay and Dr. Val{\'e}rie Jahns for her efforts towards faster automated analysis of the obtained results. Nick Verhavert is acknowledged for his assistance with the NanoBiT{\textregistered} assay. Diego Rodriguez-Soacha is acknowledged for establishing the rCB1R radioligand binding assay in our laboratory. Special thanks to Dr. Rangan Maitra and RTI International for providing the G16 coupled hCB1 and hCB2 CHO-K1 cell lines. The authors thank Nadine Yurdag{\"u}l-Hemmrich and Annette Hannawacker for excellent technical support. This project was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft under DFG DE1546/10-1). J. N. Hislop{\textquoteright}s financing support was given by NHS Grampian. The research visit of S. A. M. Steinm{\"u}ller in Dr. Hislop{\textquoteright}s laboratory was funded by the Elite Network of Bavaria (grant N° K-BM-2013-247). J. Fender and A. Tutov were supported by the International Doctoral Program “Receptor Dynamics” funded within the framework of the Elite Network of Bavaria (grant N° K-BM-2013- 247). M. H. Deventer was funded by the Research FoundationFlanders (FWO; grant 1S54521N). ",

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AU - Fender, Julia

AU - Deventer, Marie H

AU - Tutov, Anna

AU - Lorenz, Kristina

AU - Stove, Christophe P

AU - Hislop, James

AU - Decker, Michael

N1 - Acknowledgements The authors would like to acknowledge Dr. Andrea Holme for excellent technical support and the Iain Fraser Cytometry Centre (University of Aberdeen) for providing access to their equipment. The authors would like to thank Dr. Matthias Scheiner for his contributions towards the development of the calcium mobilization assay and Dr. Valérie Jahns for her efforts towards faster automated analysis of the obtained results. Nick Verhavert is acknowledged for his assistance with the NanoBiT® assay. Diego Rodriguez-Soacha is acknowledged for establishing the rCB1R radioligand binding assay in our laboratory. Special thanks to Dr. Rangan Maitra and RTI International for providing the G16 coupled hCB1 and hCB2 CHO-K1 cell lines. The authors thank Nadine Yurdagül-Hemmrich and Annette Hannawacker for excellent technical support. This project was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft under DFG DE1546/10-1). J. N. Hislop’s financing support was given by NHS Grampian. The research visit of S. A. M. Steinmüller in Dr. Hislop’s laboratory was funded by the Elite Network of Bavaria (grant N° K-BM-2013-247). J. Fender and A. Tutov were supported by the International Doctoral Program “Receptor Dynamics” funded within the framework of the Elite Network of Bavaria (grant N° K-BM-2013- 247). M. H. Deventer was funded by the Research FoundationFlanders (FWO; grant 1S54521N).

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N2 - The cannabinoid 2 receptor (CB2R) has high therapeutic potential for multiple pathogenic processes, such as neuroinflammation. Pathway-selective ligands are needed to overcome the lack of clinical success and to elucidate correlations between pathways and their respective therapeutic effects. Herein, we report the design and synthesis of a photoswitchable scaffold based on the privileged structure of benzimidazole and its application as a functionally selective CB2R "efficacy-switch". Benzimidazole azo-arenes offer huge potential for the broad extension of photopharmacology to a wide range of optically addressable biological targets. We used this scaffold to develop compound 10d, a "trans-on" agonist, which serves as a molecular probe to study the β-arrestin2 (βarr2) pathway at CB2R. βArr2 bias was observed in CB2R internalization and ßarr2 recruitment, while no activation occurred when looking at Gα16 or mini-Gαi. Overall, compound 10d is the first light-dependent functionally selective agonist to investigate the complex mechanisms of CB2R-βarr2 dependent endocytosis.

AB - The cannabinoid 2 receptor (CB2R) has high therapeutic potential for multiple pathogenic processes, such as neuroinflammation. Pathway-selective ligands are needed to overcome the lack of clinical success and to elucidate correlations between pathways and their respective therapeutic effects. Herein, we report the design and synthesis of a photoswitchable scaffold based on the privileged structure of benzimidazole and its application as a functionally selective CB2R "efficacy-switch". Benzimidazole azo-arenes offer huge potential for the broad extension of photopharmacology to a wide range of optically addressable biological targets. We used this scaffold to develop compound 10d, a "trans-on" agonist, which serves as a molecular probe to study the β-arrestin2 (βarr2) pathway at CB2R. βArr2 bias was observed in CB2R internalization and ßarr2 recruitment, while no activation occurred when looking at Gα16 or mini-Gαi. Overall, compound 10d is the first light-dependent functionally selective agonist to investigate the complex mechanisms of CB2R-βarr2 dependent endocytosis.

KW - benzimidazoles

KW - G protein-coupled receptor

KW - optical control

KW - photopharmacology

KW - biased ligand

U2 - 10.1002/anie.202306176

DO - 10.1002/anie.202306176

M3 - Article

C2 - 37269130

SN - 1433-7851

VL - 62

JO - Angewandte Chemie International Edition

JF - Angewandte Chemie International Edition

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ER -

Visible-Light Photoswitchable Benzimidazole Azo-Arenes as beta-Arrestin2-Biased Selective Cannabinoid 2 Receptor Agonists

Abstract

Bibliographical note

Data Availability Statement

Keywords

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