Synthesis and biological evaluation of novel tanshinone IIA derivatives for treating pain

Chin J Nat Med. 2018 Feb;16(2):113-124. doi: 10.1016/S1875-5364(18)30037-2.

Abstract

Due to ineffectiveness and side effects of existing analgesics, chronic pain has become one of the most complex and difficult problems in the clinic. Monoacylglycerol lipase (MAGL) is an essential hydrolase in the endocannabinoid system and has been identified as a potential target for the treatment of pain. In the present study, we designed and synthesized twelve tanshinone IIA analogs and screened their activity against MAGL. Selected compounds were tested for analgesic activity in vivo, with the acetic acid writhing test model. Among the test compounds, compound III-3 (IC50 120 nmol·L-1) showed significant activity against MAGL and ameliorated the clinical progression in the mouse pain model. Additionally, compound III-3, substitution with N-methyl-2-morpholinoacetamide, demonstrated improved solubility relative to tanshinone IIA.

Keywords: Analgesic activity; MAGL inhibitors; Tanshinone IIA.

MeSH terms

  • Abietanes / administration & dosage*
  • Abietanes / chemical synthesis*
  • Abietanes / chemistry
  • Analgesics / administration & dosage*
  • Analgesics / chemical synthesis*
  • Analgesics / chemistry
  • Animals
  • Chronic Pain / drug therapy*
  • Chronic Pain / enzymology
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred ICR
  • Monoacylglycerol Lipases / antagonists & inhibitors
  • Monoacylglycerol Lipases / metabolism
  • Structure-Activity Relationship

Substances

  • Abietanes
  • Analgesics
  • Enzyme Inhibitors
  • tanshinone
  • Monoacylglycerol Lipases