1. New Insights into Bitopic Orthosteric/Allosteric Ligands of Cannabinoid Receptor Type 2
- Author
-
Rebecca Ferrisi, Beatrice Polini, Caterina Ricardi, Francesca Gado, Kawthar A. Mohamed, Giovanna Baron, Salvatore Faiella, Giulio Poli, Simona Rapposelli, Giuseppe Saccomanni, Giancarlo Aldini, Grazia Chiellini, Robert B. Laprairie, Clementina Manera, and Gabriella Ortore
- Subjects
Organic Chemistry ,cannabinoid receptor type 2 ,General Medicine ,human microglial cells ,Settore CHIM/08 - Chimica Farmaceutica ,Catalysis ,Computer Science Applications ,drug discovery ,Inorganic Chemistry ,docking ,endocannabinoid system ,allosteric modulators ,dualsteric/bitopic ,anti-inflammatory activity ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy - Abstract
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.
- Published
- 2023
- Full Text
- View/download PDF