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 JR compounds, which combine the pharmacophoric portion of the CB2R positive allosteric modulator (PAM), EC21a, with that of the CB2R selective orthosteric agonist LV62, both synthesized in our laboratories. The functional examination enabled us to identify JR14a, JR22a, and JR64a 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 JR22a 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 JR22a. Finally, the potential of JR22a to prevent neuroinflammation was investigated on a human microglial cell inflammatory model.

Automated summary

We have developed a new generation of ligands (JR compounds) that target the CB2R. These compounds combine the pharmacophoric portion of CB2R positive allosteric modulator (EC21a) with that of CB2R selective orthosteric agonist (LV62). Among the tested compounds, JR22a showed dualsteric behavior as a CB2R ligand. Computational studies confirmed the binding mode of JR22a at CB2R, and its potential to prevent neuroinflammation was investigated using a human microglial cell model.