OBJECTIVE Investigate the inhibitory effects of coptisine and its derivatives on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) to study the relationship between the bioactivities and the structures.METHODS AChE were derived from rat brain and BuChE were derived from human plasma, the inhibitory activities of the derivatives were detected through AChE inhibitor and BuChE inhibitor screening models and the 50% inhibitory concentration (IC50) was calculated, the IC50 values of these compounds was used in the SAR analysis.RESULTS Coptisine exhibited moderate cholinesterases (ChEs) inhibitory effect with IC50 values of 25.74 μmol· L-1 for AChE and 4.62 μ mol· L-1 for BuChE.Respectively, most of its derivatives exerted higher AChE inhibitory activities, J34720, J34734, J34725, J34726, J34728, J35247, J35366 exhibited inhibitory effects with IC50 values below 10 →mol·L-1 for ChEs, derivate J34726 exhibited good inhibitory effects with IC50 values 2.18 →mol·L-1 for AChE and 2.66 μmol· L-1 for BuChE.The Nitrogen and oxygen atoms present in the molecular were essential in the interaction of coptisine and ACHE;derivative with aikyl side chain of C-13 had better AChE inhibitory effect and the effect increased along with the extension of carbon chain ; the presence of side chain having 3-5 carbons decreased BuChE inhibitory effect, since the active site gorge of BuChE contained less aromatic amino acid residues.CONCLUSION AChE inhibitors are the most successful drugs for treatment of Alzheimer s disease (AD).Coptisine derivatives exhibited potent ChEs inhibitory activities, J34726 showed the most potent inhibitory activity among them.SAR study revealed that alkyl side chain at C-13 position strengthen the AChE inhibition.The findings of this study provide important information relating the chemical structure of coptisine derivatives to their inhibitory activity of ChE.This understanding would facilitate the structural modification and exploitation of coptisine derivatives as ChE inhibitor for AD treatment.