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


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
Early online date25 Feb 2023
Publication statusE-pub ahead of print - 25 Feb 2023


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


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