Cannabidiol Analogue CIAC001 for the Treatment of Morphine-Induced Addiction by Targeting PKM2.
Sha JinCong LinYibo WangHongshuang WangXin WenPeng XiaoXiaodong LiYinghua PengJin-Peng SunYuyuan LuXiaohui WangPublished in: Journal of medicinal chemistry (2023)
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.
Keyphrases
- high glucose
- public health
- protein protein
- diabetic rats
- small molecule
- endothelial cells
- emergency department
- traumatic brain injury
- rheumatoid arthritis
- inflammatory response
- spinal cord
- brain injury
- systemic lupus erythematosus
- combination therapy
- pain management
- blood brain barrier
- tyrosine kinase
- cognitive impairment
- disease activity
- smoking cessation
- protein kinase