engleski

Resolution of 3-hydroxyquinuclidinium enantiomers and inhibition of cholinesterases

Racemic quinuclidin-3-il acetate was synthesized by esterification of quinuclidin-3- ol with acetic anhydride. (R)- and (S)- quinuclidin-3-il acetates were obtained by resolution of the racemate with L- and D- tartaric acid. Chiral (R)- and (S)-quinuclidin- 3-ols were prepared by hydrolysis of (R)- and (S)-acetates. (R)-N-methyl-3-hydroxyqui- nuclidinium iodide (R-QOH) and (S)-N-methyl-3- hydroxyqui-nuclidinium iodide (S-QOH) were synthesized by quaternisation of appropriate chiral alcohol with methyl iodide. The structures and purity of all compounds were determined by IR, one- and two-dimensional NMR, and optical purity by optical rotation measurement. R- and S-QOH were then tested for inhibition of human erythrocyte acetylcholinesterase (AChE ; EC 3.1.1.7) and serum butyrylcholinesterase (BChE ; EC 3.1.1.8). Reversible inhibition of AChE or BChE by R- and S-QOH (1.0 - 10 mM) was measured at 37 oC in 0.1 M phosphate buffer pH=7.4 with acetylthiocholine as the substrate (0.1 to 5.0 mM). The dissociation constants of enzyme- inhibitor complexes were determined from Hunter-Downs plots. The dissociation constants for AChE and both enantiomers were the same (1.2 mM). The dissociation constants for BChE were 2.1 and 0.87 mM for R- and S-QOH respectively.

3-hydroxyquinuclidinium enantiomers

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