Structural basis of selective cannabinoid CB<sub>2</sub> receptor activation.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 36922494.
- Also identified by DOI 10.1038/s41467-023-37112-9 and PMC identifier 10017709.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Cannabinoid CB<sub>2</sub> receptor (CB<sub>2</sub>R) agonists are investigated as therapeutic agents in the clinic. However, their molecular mode-of-action is not fully understood. Here, we report the discovery of LEI-102, a CB<sub>2</sub>R agonist, used in conjunction with three other CBR ligands (APD371, HU308, and CP55,940) to investigate the selective CB<sub>2</sub>R activation by binding kinetics, site-directed mutagenesis, and cryo-EM studies. We identify key residues for CB<sub>2</sub>R activation. 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. Favorable physico-chemical properties of LEI-102 enable oral efficacy in a chemotherapy-induced nephropathy model. This study delineates the molecular mechanism of CB<sub>2</sub>R activation by selective agonists and highlights the role of lipophilicity in CB<sub>2</sub>R engagement. This may have implications for GPCR drug design and sheds light on their activation by endogenous ligands.
Medical subject headings
- Cannabinoid Receptor Agonists
- Cannabinoids