New Insights into Bitopic Orthosteric/Allosteric Ligands of Cannabinoid Receptor Type 2.

Very recently, we have developed a new generation of ligands targeting the cannabinoid receptor type 2 (CB2R), namely compounds, which combine the pharmacophoric portion of the CB2R positive allosteric modulator (PAM), , with that of the CB2R selective orthosteric agonist , both synthesized in our laboratories. The functional examination enabled us to identify , , and as the most promising compounds of the series. In the current study, we focused on the assessment of the bitopic (dualsteric) nature of these three compounds. Experiments in cAMP assays highlighted that only behaves as a CB2R bitopic (dualsteric) ligand. In parallel, computational studies helped us to clarify the binding mode of these three compounds at CB2R, confirming the bitopic (dualsteric) nature of . Finally, the potential of to prevent neuroinflammation was investigated on a human microglial cell inflammatory model.