2. Academic Validation
  3. Discovery of a CB2 and 5-HT1A receptor dual agonist for the treatment of depression and anxiety

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

  • Eur J Med Chem. 2023 Dec 14:265:116048. doi: 10.1016/j.ejmech.2023.116048.
Wenjiao Yang 1,  Xudong Gong 2,  Haiguo Sun 3,  Chunhui Wu 2,  Jin Suo 3,  Jing Ji 1,  Xiangrui Jiang 4,  Jingshan Shen 5,  Yang He 6,  Haji Akber Aisa 7
Affiliations

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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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-HT1AR dual agonist, albeit with some undesired antagonist activity for CB1R. It demonstrated significant CB2R partial agonism while maintaining a level of 5-HT1AR 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.

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