3-hydroxyquinuclidinium derivatives: synthesis of compounds and inhibitionof acetylcholinesterase

Four compounds were prepared: 3-hydroxy-1-methylquinuclidinium iodide (I), 3-(N,N-dimethylcarbamoyloxy)-1-methylquinuclidinum iodide (II), and two con jugates of I and II with 2-hydroxyiminomethyl-3-methylimidazole in which tw o parts of the molecule were linked by -CH2-O-CH2- (III and IV). III and IV are new compounds and their synthesis and physical data were given. All co mpounds were tested as inhibitors of human erythrocyte acetylcholinesterase (EC 3.1.1.7, AChE). The enzyme activity was measured in 0.1 M phosphate bu ffer (pH 7.4) at 10 and 37 degrees C with acetylthiocholine (ATCh) as the s ubstrate. The obtained enzyme/inhibitor dissociation constants were between 0.05 and 0.5 mM at 10 degrees C and between 0.2 and 0.6 mM at 37 degrees C . At both temperatures compounds III and IV had higher affinities for the e nzyme than compounds I and II and this difference was more pronounced at 10 than at 37 degrees C. The carbamates II and IV were also progressive AChE inhibitors. For compound II the rate constants of inhibition were 6300 and 2020 M-1 min(-1) at 37 and 10 degrees C, respectively. Compound IV was a ve ry weak carbamoylating agent with rate constants of inhibition of 100 and 6 3 M-1 min(-1) at 37 and 10 degrees C, respectively. The oxime group in comp ounds III and IV hydrolyzed ATCh at rates of 23 and 3.2 M-1 min(-1) at 37 a nd 10 degrees C, respectively. (C) 1999 Elsevier Science Ireland Ltd. All r ights reserved.