Bridging the Binding Sites 2.0: Photoswitchable Dualsteric Ligands for the Cannabinoid 2 Receptor

Sophie A M Steinmüller; Anna Tutov; James N Hislop; Michael Decker

doi:10.1021/acschemneuro.3c00509

Bridging the Binding Sites 2.0: Photoswitchable Dualsteric Ligands for the Cannabinoid 2 Receptor

Sophie A M Steinmüller, Anna Tutov, James N Hislop, Michael Decker

University of Würzburg

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

Abstract

The cannabinoid receptor 2 (CB 2R) has high, unexploited therapeutic potential in several central nervous system disorders due to its involvement in neuroinflammatory processes and pathologies like neurodegeneration. Dualsteric/bitopic ligands are currently developed to achieve receptor subtype selectivity and biased signaling. To obtain a molecular tool compound with photoswitchable potential dualsteric properties, we applied two different approaches to link a positive allosteric modulator with an orthosteric agonist via a photochromic unit. We characterized the photophysical properties of all compounds and determined efficacy in internalization, calcium mobilization, and BRET studies. We report the first potentially dualsteric photoswitchable ligand for studying molecular mechanisms of CB 2R-associated pathologies. Compound 17- para is a submicromolar " cis-on" agonist with >10-fold higher potency compared to its trans photoisomer and allows high spatiotemporal control of CB 2R activation.

Original language	English
Pages (from-to)	3737-3744
Number of pages	8
Journal	ACS Chemical Neuroscience
Volume	14
Issue number	20
Early online date	4 Oct 2023
DOIs	https://doi.org/10.1021/acschemneuro.3c00509
Publication status	Published - 18 Oct 2023

Bibliographical note

Acknowledgments

Special thanks to Dr. Rangan Maitra and RTI International for providing the Gα16-coupled hCB1 and hCB2 CHO-K1 cell lines. This project was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft) under DFG DE1546/10-1. J.N.H.’s financing support was given by NHS Grampian and Friends of Anchor. The research visit of S.A.M.S. in J.N.H.’s laboratory was funded by the Elite Network of Bavaria. A.T. was supported by the International Doctoral Program “Receptor Dynamics” funded within the framework of the Elite Network of Bavaria (Grant K-BM-2013-247).

Keywords

Photopharmacology
heterobivalent ligand
G protein-coupled receptor
optical control
CB2 agonist
azobenzene

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Cite this

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title = "Bridging the Binding Sites 2.0: Photoswitchable Dualsteric Ligands for the Cannabinoid 2 Receptor",

abstract = "The cannabinoid receptor 2 (CB 2R) has high, unexploited therapeutic potential in several central nervous system disorders due to its involvement in neuroinflammatory processes and pathologies like neurodegeneration. Dualsteric/bitopic ligands are currently developed to achieve receptor subtype selectivity and biased signaling. To obtain a molecular tool compound with photoswitchable potential dualsteric properties, we applied two different approaches to link a positive allosteric modulator with an orthosteric agonist via a photochromic unit. We characterized the photophysical properties of all compounds and determined efficacy in internalization, calcium mobilization, and BRET studies. We report the first potentially dualsteric photoswitchable ligand for studying molecular mechanisms of CB 2R-associated pathologies. Compound 17- para is a submicromolar {"} cis-on{"} agonist with >10-fold higher potency compared to its trans photoisomer and allows high spatiotemporal control of CB 2R activation. ",

keywords = "Photopharmacology, heterobivalent ligand, G protein-coupled receptor, optical control, CB2 agonist, azobenzene",

author = "Steinm{\"u}ller, {Sophie A M} and Anna Tutov and Hislop, {James N} and Michael Decker",

note = "Acknowledgments Special thanks to Dr. Rangan Maitra and RTI International for providing the Gα16-coupled hCB1 and hCB2 CHO-K1 cell lines. This project was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft) under DFG DE1546/10-1. J.N.H.{\textquoteright}s financing support was given by NHS Grampian and Friends of Anchor. The research visit of S.A.M.S. in J.N.H.{\textquoteright}s laboratory was funded by the Elite Network of Bavaria. A.T. was supported by the International Doctoral Program “Receptor Dynamics” funded within the framework of the Elite Network of Bavaria (Grant K-BM-2013-247).",

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N1 - Acknowledgments Special thanks to Dr. Rangan Maitra and RTI International for providing the Gα16-coupled hCB1 and hCB2 CHO-K1 cell lines. This project was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft) under DFG DE1546/10-1. J.N.H.’s financing support was given by NHS Grampian and Friends of Anchor. The research visit of S.A.M.S. in J.N.H.’s laboratory was funded by the Elite Network of Bavaria. A.T. was supported by the International Doctoral Program “Receptor Dynamics” funded within the framework of the Elite Network of Bavaria (Grant K-BM-2013-247).

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N2 - The cannabinoid receptor 2 (CB 2R) has high, unexploited therapeutic potential in several central nervous system disorders due to its involvement in neuroinflammatory processes and pathologies like neurodegeneration. Dualsteric/bitopic ligands are currently developed to achieve receptor subtype selectivity and biased signaling. To obtain a molecular tool compound with photoswitchable potential dualsteric properties, we applied two different approaches to link a positive allosteric modulator with an orthosteric agonist via a photochromic unit. We characterized the photophysical properties of all compounds and determined efficacy in internalization, calcium mobilization, and BRET studies. We report the first potentially dualsteric photoswitchable ligand for studying molecular mechanisms of CB 2R-associated pathologies. Compound 17- para is a submicromolar " cis-on" agonist with >10-fold higher potency compared to its trans photoisomer and allows high spatiotemporal control of CB 2R activation.

AB - The cannabinoid receptor 2 (CB 2R) has high, unexploited therapeutic potential in several central nervous system disorders due to its involvement in neuroinflammatory processes and pathologies like neurodegeneration. Dualsteric/bitopic ligands are currently developed to achieve receptor subtype selectivity and biased signaling. To obtain a molecular tool compound with photoswitchable potential dualsteric properties, we applied two different approaches to link a positive allosteric modulator with an orthosteric agonist via a photochromic unit. We characterized the photophysical properties of all compounds and determined efficacy in internalization, calcium mobilization, and BRET studies. We report the first potentially dualsteric photoswitchable ligand for studying molecular mechanisms of CB 2R-associated pathologies. Compound 17- para is a submicromolar " cis-on" agonist with >10-fold higher potency compared to its trans photoisomer and allows high spatiotemporal control of CB 2R activation.

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Bridging the Binding Sites 2.0: Photoswitchable Dualsteric Ligands for the Cannabinoid 2 Receptor

Abstract

Bibliographical note

Keywords

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