Structural basis of selective cannabinoid CB2 receptor activation

Xiaoting Li; Hao Chang; Jara Bouma; Laura V de Paus; Partha Mukhopadhyay; Janos Paloczi; Mohammed Mustafa; Cas van der Horst; Sanjay Sunil Kumar; Lijie Wu; Yanan Yu; Richard J B H N van den Berg; Antonius P A Janssen; Aron Lichtman; Zhi-Jie Liu; Pal Pacher; Mario van der Stelt; Laura H Heitman; Tian Hua

doi:10.1038/s41467-023-37112-9

Structural basis of selective cannabinoid CB₂ receptor activation

Nat Commun. 2023 Mar 15;14(1):1447. doi: 10.1038/s41467-023-37112-9.

Authors

Xiaoting Li^#¹, Hao Chang^#^{1

2}, Jara Bouma^#³, Laura V de Paus⁴, Partha Mukhopadhyay⁵, Janos Paloczi⁵, Mohammed Mustafa⁶, Cas van der Horst³, Sanjay Sunil Kumar³, Lijie Wu^{1

2}, Yanan Yu^{1

2}, Richard J B H N van den Berg⁴, Antonius P A Janssen⁴, Aron Lichtman⁶, Zhi-Jie Liu^{7

8}, Pal Pacher⁹, Mario van der Stelt¹⁰, Laura H Heitman¹¹, Tian Hua^{12

13}

Affiliations

¹ iHuman Institute, ShanghaiTech University, Shanghai, 201210, China.
² School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
³ Division of Drug Discovery and Safety, Leiden Academic Center for Drug Research, Leiden University, Oncode Institute, Leiden, the Netherlands.
⁴ Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Oncode Institute, Leiden, the Netherlands.
⁵ Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute of Health/National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, USA.
⁶ Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
⁷ iHuman Institute, ShanghaiTech University, Shanghai, 201210, China. liuzhj@shanghaitech.edu.cn.
⁸ School of Life Science and Technology, ShanghaiTech University, Shanghai, China. liuzhj@shanghaitech.edu.cn.
⁹ Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute of Health/National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, USA. pacher@mail.nih.gov.
¹⁰ Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Oncode Institute, Leiden, the Netherlands. m.van.der.stelt@chem.leidenuniv.nl.
¹¹ Division of Drug Discovery and Safety, Leiden Academic Center for Drug Research, Leiden University, Oncode Institute, Leiden, the Netherlands. l.h.heitman@lacdr.leidenuniv.nl.
¹² iHuman Institute, ShanghaiTech University, Shanghai, 201210, China. huatian@shanghaitech.edu.cn.
¹³ School of Life Science and Technology, ShanghaiTech University, Shanghai, China. huatian@shanghaitech.edu.cn.

^# Contributed equally.

Abstract

Cannabinoid CB₂ receptor (CB₂R) 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 CB₂R agonist, used in conjunction with three other CBR ligands (APD371, HU308, and CP55,940) to investigate the selective CB₂R activation by binding kinetics, site-directed mutagenesis, and cryo-EM studies. We identify key residues for CB₂R 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 CB₂R activation by selective agonists and highlights the role of lipophilicity in CB₂R engagement. This may have implications for GPCR drug design and sheds light on their activation by endogenous ligands.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Cannabinoid Receptor Agonists* / pharmacology
Cannabinoids* / pharmacology
Receptor, Cannabinoid, CB1 / genetics
Receptor, Cannabinoid, CB2 / genetics
Receptors, Cannabinoid

Substances

HU 308
3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol
Cannabinoid Receptor Agonists
Receptors, Cannabinoid
Cannabinoids
Receptor, Cannabinoid, CB1
Receptor, Cannabinoid, CB2