THC exerts its therapeutic effects mostly via the G protein-coupled receptors (GPCRs) cannabinoid CB 1 and CB 2 receptors (CB 1R and CB 2R), which have 68% sequence identity in their seven transmembrane (TM) domains 11.

This may have implications for GPCR drug design and sheds light on their activation by endogenous ligands. This study delineates the molecular mechanism of CB 2R activation by selective agonists and highlights the role of lipophilicity in CB 2R engagement. Favorable physico-chemical properties of LEI-102 enable oral efficacy in a chemotherapy-induced nephropathy model. Highly lipophilic HU308 and the endocannabinoids, but not the more polar LEI-102, APD371, and CP55,940, reach the binding pocket through a membrane channel in TM1-TM7. We identify key residues for CB 2R activation.

Here, we report the discovery of LEI-102, a CB 2R agonist, used in conjunction with three other CBR ligands (APD371, HU308, and CP55,940) to investigate the selective CB 2R activation by binding kinetics, site-directed mutagenesis, and cryo-EM studies.

However, their molecular mode-of-action is not fully understood. Nature Communications volume 14, Article number: 1447 ( 2023)Ĭannabinoid CB 2 receptor (CB 2R) agonists are investigated as therapeutic agents in the clinic. Structural basis of selective cannabinoid CB 2 receptor activation

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