Bridging the Binding Sites: Dualsteric Ligands for the Cannabinoid 2 Receptor (CB2R)

Anna Tutov; Sophie A. M. Steinmüller; Yesid A. Ramírez; Christine E. Jack; Diego A. Rodríguez-Soacha; Christoph Sotriffer; James N. Hislop; Michael Decker

doi:10.1002/adtp.202200260

Bridging the Binding Sites: Dualsteric Ligands for the Cannabinoid 2 Receptor (CB2R)

Anna Tutov, Sophie A. M. Steinmüller, Yesid A. Ramírez, Christine E. Jack, Diego A. Rodríguez-Soacha, Christoph Sotriffer, James N. Hislop, Michael Decker^* (Corresponding Author)

^*Corresponding author for this work

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

Abstract

Abstract The cannabinoid receptor subtype 2 (CB2R) is rapidly upregulated in neuroinflammatory processes and respective agonists have a high potential to combat several central nervous system disorders related to neuroinflammation and neurodegeneration. As a new strategy for ligand design, dualsteric binding is applied by chemically combining a positive allosteric modulator with an orthosteric ligand. The resulting two sets of potential dualsteric (or bitopic) ligands with different chain lengths of two to five methylene groups are evaluated in [3H]CP55940 binding studies to determine receptor affinity at CB1R and CB2R. Calcium mobilization, receptor endocytosis and BRET assays determine their efficacy and identify compounds of set B to act as agonists with efficacy higher than the reference compound in G protein mediated calcium signaling. Pharmacological evaluation and docking studies support the dualsteric nature of binding of the herein presented compounds.

Original language	English
Article number	2200260
Number of pages	11
Journal	Advanced Therapeutics
Early online date	25 Feb 2023
DOIs	https://doi.org/10.1002/adtp.202200260
Publication status	E-pub ahead of print - 25 Feb 2023

Keywords

efficacy
G protein-coupled receptor
heterobivalent
positive allosteric modulator

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© 2023 The Authors. Advanced Therapeutics published by Wiley-VCH GmbH This is an open access article under the terms of the Creative Commons Attribution-NonCommercial 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/
Final published version, 1.38 MBLicence: CC BY-NC

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title = "Bridging the Binding Sites: Dualsteric Ligands for the Cannabinoid 2 Receptor (CB2R)",

abstract = "Abstract The cannabinoid receptor subtype 2 (CB2R) is rapidly upregulated in neuroinflammatory processes and respective agonists have a high potential to combat several central nervous system disorders related to neuroinflammation and neurodegeneration. As a new strategy for ligand design, dualsteric binding is applied by chemically combining a positive allosteric modulator with an orthosteric ligand. The resulting two sets of potential dualsteric (or bitopic) ligands with different chain lengths of two to five methylene groups are evaluated in [3H]CP55940 binding studies to determine receptor affinity at CB1R and CB2R. Calcium mobilization, receptor endocytosis and BRET assays determine their efficacy and identify compounds of set B to act as agonists with efficacy higher than the reference compound in G protein mediated calcium signaling. Pharmacological evaluation and docking studies support the dualsteric nature of binding of the herein presented compounds.",

keywords = "efficacy, G protein-coupled receptor, heterobivalent, positive allosteric modulator",

author = "Anna Tutov and Steinm{\"u}ller, {Sophie A. M.} and Ram{\'i}rez, {Yesid A.} and Jack, {Christine E.} and Rodr{\'i}guez-Soacha, {Diego A.} and Christoph Sotriffer and Hislop, {James N.} and Michael Decker",

note = "Acknowledgements This project was financially supported by the German Research Foundation (Deutsche Forschungsgemeinschaft under DFG DE1546/10-1). Gratitude is expressed to the International Doctorate Program “Receptor Dynamics” of the Elite Network of Bavaria (ENB) for financial support of A.T. and S.A.M.S. (grant No. K-BM-2013-247). Y.A.R. was granted a scholarship by the German Academic Exchange Service (Deutscher Akademischer Austauschdienst, DAAD) program “Research stays for university academics and scientists.” D.A.R.-S. was awarded a Ph.D. scholarship by the DAAD. J.N.H. was financially supported by NHS Grampian. Furthermore, the authors thank Professor Dr. Kristina Lorenz (Institute of Pharmacology and Toxicology, University of W{\"u}rzburg) for enabling them to conduct in vitro experiments in her laboratory. Open access funding enabled and organized by Projekt DEAL.",

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AU - Steinmüller, Sophie A. M.

AU - Ramírez, Yesid A.

AU - Jack, Christine E.

AU - Rodríguez-Soacha, Diego A.

AU - Sotriffer, Christoph

AU - Hislop, James N.

AU - Decker, Michael

N1 - Acknowledgements This project was financially supported by the German Research Foundation (Deutsche Forschungsgemeinschaft under DFG DE1546/10-1). Gratitude is expressed to the International Doctorate Program “Receptor Dynamics” of the Elite Network of Bavaria (ENB) for financial support of A.T. and S.A.M.S. (grant No. K-BM-2013-247). Y.A.R. was granted a scholarship by the German Academic Exchange Service (Deutscher Akademischer Austauschdienst, DAAD) program “Research stays for university academics and scientists.” D.A.R.-S. was awarded a Ph.D. scholarship by the DAAD. J.N.H. was financially supported by NHS Grampian. Furthermore, the authors thank Professor Dr. Kristina Lorenz (Institute of Pharmacology and Toxicology, University of Würzburg) for enabling them to conduct in vitro experiments in her laboratory. Open access funding enabled and organized by Projekt DEAL.

PY - 2023/2/25

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N2 - Abstract The cannabinoid receptor subtype 2 (CB2R) is rapidly upregulated in neuroinflammatory processes and respective agonists have a high potential to combat several central nervous system disorders related to neuroinflammation and neurodegeneration. As a new strategy for ligand design, dualsteric binding is applied by chemically combining a positive allosteric modulator with an orthosteric ligand. The resulting two sets of potential dualsteric (or bitopic) ligands with different chain lengths of two to five methylene groups are evaluated in [3H]CP55940 binding studies to determine receptor affinity at CB1R and CB2R. Calcium mobilization, receptor endocytosis and BRET assays determine their efficacy and identify compounds of set B to act as agonists with efficacy higher than the reference compound in G protein mediated calcium signaling. Pharmacological evaluation and docking studies support the dualsteric nature of binding of the herein presented compounds.

AB - Abstract The cannabinoid receptor subtype 2 (CB2R) is rapidly upregulated in neuroinflammatory processes and respective agonists have a high potential to combat several central nervous system disorders related to neuroinflammation and neurodegeneration. As a new strategy for ligand design, dualsteric binding is applied by chemically combining a positive allosteric modulator with an orthosteric ligand. The resulting two sets of potential dualsteric (or bitopic) ligands with different chain lengths of two to five methylene groups are evaluated in [3H]CP55940 binding studies to determine receptor affinity at CB1R and CB2R. Calcium mobilization, receptor endocytosis and BRET assays determine their efficacy and identify compounds of set B to act as agonists with efficacy higher than the reference compound in G protein mediated calcium signaling. Pharmacological evaluation and docking studies support the dualsteric nature of binding of the herein presented compounds.

KW - efficacy

KW - G protein-coupled receptor

KW - heterobivalent

KW - positive allosteric modulator

U2 - 10.1002/adtp.202200260

DO - 10.1002/adtp.202200260

M3 - Article

JO - Advanced Therapeutics

JF - Advanced Therapeutics

M1 - 2200260

ER -

Bridging the Binding Sites: Dualsteric Ligands for the Cannabinoid 2 Receptor (CB2R)

Abstract

Keywords

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