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

• Published in: Advanced therapeutics 2023-04, Vol.6 (4), p.n/a
• Main Authors: Tutov, Anna, Steinmüller, Sophie A. M., Ramírez, Yesid A., Jack, Christine E., Rodríguez‐Soacha, Diego A., Sotriffer, Christoph, Hislop, James N., Decker, Michael
• Format: Article
• Language: English
• Subjects: efficacy; G protein‐coupled receptor; heterobivalent; positive allosteric modulator
• ISSN: 2366-3987; 2366-3987
• DOI: 10.1002/adtp.202200260

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. By chemical combination of an orthosteric ligand and a positive allosteric modulator for the cannabinoid receptor subtype 2 (CB2R), two sets of putatively heterobivalent, dualsteric ligands are obtained. The compounds are CB2R‐selective. Investigation into G protein‐signaling shows remarkable binding and signaling profiles, such as an efficacy higher than the reference compound's one (“superagonism”) of compounds of set B compounds.