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Resolution of N-benzyl-3-hydroxyquinuclidinium enantiomers and their affinity for cholinesterases

In our previous study quinuclidinium compounds were shown to protect acetylcholinesterase against phosphorylation by soman and VX, and to protect mice against soman by increasing its LD50. In this study (R)- and (S)-enantiomers of N-benzyl-3-hydroxyquinuclidinium chloride (QOHBz) were prepared in order to test the difference in their affinity for cholinesterases. Chiral (R)- and (S)-quinuclidin-3-ols were prepared by resolution of racemic quinuclidin-3-il acetate with L- and D-tartaric acid followed by hydrolysis. (R)-N-benzyl-3-hydroxyquinuclidinium chloride (R-QOHBz) and (S)-N-benzyl-3-hydroxyquinuclidinium chloride (S-QOHBz) were synthesized by quaternization of the appropriate chiral alcohol with benzyl chloride. The structure and purity of all compounds were determined by MS, IR, one- and two-dimensional NMR, and optical purities by optical rotation measurement. R- and S-QOHBz were tested for inhibition of human erythrocyte acetylcholinesterase (AChE) and serum butyrylcholinesterase (BChE). Reversible inhibition of AChE or BChE by R- and S-QOHBz was measured with acetylthiocholine as substrate (0.1-1.0 mM). The dissociation constants of enzyme-inhibitor complexes were determined from Hunter-Downs plots. The dissociation constants of AChE were 0.26 and 0.67 mM for (S)- and (R)-enantiomers and those of BChE were 0.053 and 0.084 mM for (S)- and (R)-enantiomers respectively. R- and S-QOHBz have higher affinities for AChE and BChE than their N-methyl analogues.

cholinesterases; N-benzyl-3-hydroxyquinuclidinium enantiomers; inhibition;

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