Structural basis of selective cannabinoid CB2 receptor activation

• Published in: Nature communications Vol. 14; no. 1; p. 1447
• Main Authors: Li, Xiaoting, Chang, Hao, Bouma, Jara, de Paus, Laura V., Mukhopadhyay, Partha, Paloczi, Janos, Mustafa, Mohammed, van der Horst, Cas, Kumar, Sanjay Sunil, Wu, Lijie, Yu, Yanan, van den Berg, Richard J. B. H. N., Janssen, Antonius P. A., Lichtman, Aron, Liu, Zhi-Jie, Pacher, Pal, van der Stelt, Mario, Heitman, Laura H., Hua, Tian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15-03-2023; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 631/154/436/2387; 631/535/1258; 631/92/613; 64/60; 82/80; 82/83; Activation analysis; Agonists; Binding; Cannabinoid CB2 receptors; Chemical properties; Chemotherapy; Drug development; G protein-coupled receptors; Humanities and Social Sciences; Kinetics; Ligands; Lipophilic; Lipophilicity; multidisciplinary; Nephropathy; Pharmacology; Physicochemical properties; Receptor mechanisms; Receptors; Science; Science (multidisciplinary); Site-directed mutagenesis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-37112-9

Cannabinoid CB
2
receptor (CB
2
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
2
R agonist, used in conjunction with three other CBR ligands (APD371, HU308, and CP55,940) to investigate the selective CB
2
R activation by binding kinetics, site-directed mutagenesis, and cryo-EM studies. We identify key residues for CB
2
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
2
R activation by selective agonists and highlights the role of lipophilicity in CB
2
R engagement. This may have implications for GPCR drug design and sheds light on their activation by endogenous ligands.
Cannabinoid CB
2
receptor (CB
2
R) agonists are investigated as therapeutic agents in the clinic. Here, authors report the discovery of LEI-102, a CB
2
R agonist, used in conjunction with three other CBR ligands (APD371, HU308, and CP55,940) to investigate selective CB
2
R activation.