engleski

Enantiomers of quinuclidin-3-ol derivatives: resolution and interactions with human cholinesterases

The (R)- and (S)-enantiomers of quinuclidin-3- ol and quinuclidin-3-yl acetate as well as their quaternary N-methyl and N-benzyl derivatives were synthesized in order to study the stereoselectivity of human erythrocyte acetylcholinesterase (EC 3.1.1.7) and plasma butyrylcholinesterase (EC 3.1.1.8). The compounds were tested as substrates and/or as inhibitors of the cholinesterases. Stereoselectivity of the cholinesterases was observed in the hydrolysis of the derivatives of quinuclidin-3-yl acetate with a preference for the (R)- over (S)-enantiomers. The best substrate for both enzymes was (R)-N-methyl acetate with kcat = 2.8 x 105 min-1 and kcat = 3.0 x 104 min-1 for acetylcholinesterase and butyrylcholinesterase, respectively. Both cholinesterases were reversibly inhibited by both enantiomers of quinuclidin-3-ol derivatives but also by (S)-enantiomers of acetates. Dissociation constants of the reversible enzyme-inhibitor complexes did not show explicit enantiomeric preference of the enzymes toward the chiral quinuclidin-3-ol derivatives. (R)- and (S)-N-benzyl-3- hydroxyquinuclidinium derivatives were the best inhibitors for both enzymes.

acetylcholinesterase ; butyrylcholinesterase ; stereoselctivity ; quinuclidin-3-ols ; quinuclidin-3-yl acetates

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