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

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.