Discovery of a CB2 and 5-HT1A receptor dual agonist for the treatment of depression and anxiety

Wenjiao Yang; Xudong Gong; Haiguo Sun; Chunhui Wu; Jin Suo; Jing Ji; Xiangrui Jiang; Jingshan Shen; Yang He; Haji Akber Aisa

doi:10.1016/j.ejmech.2023.116048

Discovery of a CB₂ and 5-HT_1A receptor dual agonist for the treatment of depression and anxiety

Eur J Med Chem. 2024 Feb 5:265:116048. doi: 10.1016/j.ejmech.2023.116048. Epub 2023 Dec 14.

Authors

Wenjiao Yang¹, Xudong Gong², Haiguo Sun³, Chunhui Wu², Jin Suo³, Jing Ji¹, Xiangrui Jiang⁴, Jingshan Shen⁵, Yang He⁶, Haji Akber Aisa⁷

Affiliations

¹ State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, and Key Laboratory of Plant Resources and Chemistry of Arid Zone, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, 830011, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
² Vigonvita Shanghai Co., Ltd, Shanghai, 201210, China.
³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
⁴ University of Chinese Academy of Sciences, Beijing, 100049, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
⁵ University of Chinese Academy of Sciences, Beijing, 100049, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: shenjingshan@simm.ac.cn.
⁶ University of Chinese Academy of Sciences, Beijing, 100049, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: heyang@simm.ac.cn.
⁷ State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, and Key Laboratory of Plant Resources and Chemistry of Arid Zone, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, 830011, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: haji@ms.xjb.ac.cn.

PMID: 38150961
DOI: 10.1016/j.ejmech.2023.116048

Abstract

Cannabinoid CB₂R agonists have gained considerable attention as potential novel therapies for psychiatric disorders due to their non-psychoactive nature, in contrast to CB₁R agonists. In this study, we employed molecular docking to design and synthesize 23 derivatives of cannabidiol (CBD) with the aim of discovering potent CB₂R agonists rather than CB₂R antagonists or inverse agonists. Structure-activity relationship (SAR) investigations highlighted the critical importance of the amide group at the C-3' site and the cycloalkyl group at the C-4' site for CB₂R activation. Interestingly, three CBD derivatives, namely 2o, 6g, and 6h, exhibited substantial partial agonistic activity towards the CB₂ receptor, in contrast to the inverse agonistic property of CBD. Among these, 2o acted as a CB₂R and 5-HT_1AR dual agonist, albeit with some undesired antagonist activity for CB₁R. It demonstrated significant CB₂R partial agonism while maintaining a level of 5-HT_1AR agonistic and CB₁R antagonistic activity similar to CBD. Pharmacokinetic experiments confirmed that 2o possesses favorable pharmacokinetic properties. Behavioral studies further revealed that 2o elicits significant antidepressant-like and anxiolytic-like effects while maintaining a good safety profile.

Keywords: 5-HT(1A)R agonist; Antidepressant; Anxiolytic; CB(1)R antagonist; CB(2)R agonist.

MeSH terms

Anxiety
Cannabidiol* / pharmacology
Cannabidiol* / therapeutic use
Cannabinoid Receptor Agonists
Depression / drug therapy
Drug Inverse Agonism
Humans
Molecular Docking Simulation
Receptor, Cannabinoid, CB1
Receptor, Cannabinoid, CB2
Receptor, Serotonin, 5-HT1A*
Serotonin
Serotonin Receptor Agonists

Substances

Receptor, Serotonin, 5-HT1A
Serotonin
Cannabinoid Receptor Agonists
Cannabidiol
Serotonin Receptor Agonists
Receptor, Cannabinoid, CB2
Receptor, Cannabinoid, CB1