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 journalArticlepeer-review

3 Citations (Scopus)
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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 languageEnglish
Article number2200260
Number of pages11
JournalAdvanced Therapeutics
Issue number4
Early online date25 Feb 2023
Publication statusPublished - 13 Apr 2023

Bibliographical note

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.

Data Availability Statement

The data that support the findings of this study are available in the supplementary material of this article.


  • efficacy
  • G protein-coupled receptor
  • heterobivalent
  • positive allosteric modulator


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