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

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 [H-3]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.