3-Hydroxyquinuclidinium derivatives: synthesis of compounds and inhibition of acetylcholinesterase

Four compounds were prepared: 3-hydroxy-1-methylquinuclidinium iodide (I), 3-(N,N-dimethylcarbamoyloxy)-1-methylquinuclidinum iodide (II), and two conjugates of I and II with 2-hydroxyiminomethyl-3-methylimidazole in which two 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 compounds were tested as inhibitors of human erythrocyte acetylcholinesterase (EC 3.1.1.7, AChE). The enzyme activity was measured in 0.1 M phosphate buffer (pH 7.4) at 10 and 37°C with acetylthiocholine (ATCh) as the substrate. The obtained enzyme/inhibitor dissociation constants were between 0.05 and 0.5 mM at 10°C and between 0.2 and 0.6 mM at 37°C. At both temperatures compounds III and IV had higher affinities for the enzyme than compounds I and II and this difference was more pronounced at 10 than at 37°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°C, respectively. Compound IV was a very weak carbamoylating agent with rate constants of inhibition of 100 and 63 M−1 min−1 at 37 and 10°C, respectively. The oxime group in compounds III and IV hydrolyzed ATCh at rates of 23 and 3.2 M−1 min−1 at 37 and 10°C, respectively.