2. Academic Validation
  3. Cannabidiol Analogue CIAC001 for the Treatment of Morphine-Induced Addiction by Targeting PKM2

Cannabidiol Analogue CIAC001 for the Treatment of Morphine-Induced Addiction by Targeting PKM2

  • J Med Chem. 2023 Aug 24;66(16):11498-11516. doi: 10.1021/acs.jmedchem.3c01029.
Sha Jin 1 2 3,  Cong Lin 2,  Yibo Wang 2,  Hongshuang Wang 2,  Xin Wen 4,  Peng Xiao 4,  Xiaodong Li 5,  Yinghua Peng 6,  Jinpeng Sun 4,  Yuyuan Lu 1 3,  Xiaohui Wang 1 2 7
Affiliations

Affiliations

  • 1 School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui 230026, China.
  • 2 Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China.
  • 3 State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China.
  • 4 Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 5 Beijing Changping Huayou Hospital, Beijing 102299, China.
  • 6 State Key Laboratory for Molecular Biology of Special Economic Animal, Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, Jilin 130112, China.
  • 7 Beijing National Laboratory for Molecular Sciences, Beijing 100190, China.
PMID: 37531582 DOI: 10.1021/acs.jmedchem.3c01029
Abstract

Opioid addiction is a chronically relapsing disorder that causes critical public health problems. Currently, there is a lack of effective drug treatment. Herein, one cannabidiol derivative, CIAC001, was discovered as an effective agent for treating morphine-induced addiction. In vitro, CIAC001 exhibited significantly improved anti-neuroinflammatory activity with lower toxicity. In vivo, CIAC001 ameliorated the morphine-induced withdrawal reaction, behavioral sensitization, and conditional position preference by inhibiting morphine-induced microglia activation and neuroinflammation. Target fishing for CIAC001 by activity-based protein profiling led to the identification of Pyruvate Kinase M2 (PKM2) as the target protein. CIAC001 bound to the protein-protein interface of the PKM2 dimer and promoted the tetramerization of PKM2. Moreover, CIAC001 exhibited an anti-neuroinflammatory effect by reversing the decrease of the PKM2 tetramer and inhibiting the nuclear translocation of PKM2. In summary, this study identified CIAC001 as a lead compound in targeting PKM2 to treat morphine-induced addiction.

Figures
Products