Selective cannabinoid CB2 receptor activation in Nature Communications
This March, Jara Bouma, Cas van der Horst and Laura Heitman from the Division of Drug Discovery and Safety and Laura de Paus, Richard van den Berg, Anthe Janssen and Mario van der Stelt from the LIC joined forces to determine how some drugs can specifically target the cannabinoid CB2 receptor (CB2R) by using cryo-EM protein structures and mutational biochemistry in a multidisciplinary approach. Together with researchers from the iHuman institute (Shanghai, China), National Institute of Health and Virginia Commonwealth University (USA) they published their work in Nature Communications (https://doi.org/10.1038/s41467-023-37112-9).
In this paper, the authors investigated the mechanism of action of selective CB2R agonists by elucidating their respective cryo-EM structures. In biochemical experiments, they discovered interesting differences between the binding mode, but also the entry mechanism into the receptor. Furthermore, the newly introduced CB2R-selective agonist LEI-102 was investigated in a chemotherapy-induced nephropathy model, where it maintained its selective behavior. All together, this study described an extensive drug discovery process from compound synthesis, structural biology to in vitro and in vivo studies, which can aid in better drug design for CB2R while avoiding CB1R-mediated psychotropic side effects.
