engleski

Analysis of biscarbamate inhibition selectivity during carbamylation of human cholinesterases

Recent findings of a close correlation between butyrylcholinesterase (BChE) inhibition and cognitive improvement in patients with Alzheimer disease support the hypothesis that the selective inhibition of BChE compared to acetylcholinesterase (AChE) could represent a therapeutic advantage in comparison to the commonly used non-selective cholinesterase or AChE selective inhibition. In this sense, a good balance between AChE and BChE inhibition may result in higher efficacy throughout the course of the disease. We analysed the inhibition selectivity of three structurally related biscarbamates: bambuterol, metacarb and isocarb, very fast (inhibition rate constants in 106 M-1min-1) and selective BChE inhibitors (they inhibited AChE 2000, 960 and 80 times more slowly than BChE, respectively). Tested biscarbamates differ in the disposition of carbamate groups on the benzene ring (meta-position in bambuterol and metacarb vs. ortho-position in isocarb). The rate of cholinesterase carbamylation is determined by the entrance of carbamate and its orientation into the active site of the enzyme, and it seemed that the meta-position of carbamate groups on the benzene ring was preferred. The two times slower inhibition of BChE by metacarb when compared to the inhibition by bambuterol could be attributed to the different size in alcohol moiety of these biscarbamates (iso-propyl group of metacarb vs. tert-butyl group of bambuterol). The inhibition potency of the studied biscarbamates was analysed by studying the transition state of the carbamylation reaction using molecular modelling. The determined differences in carbamylation rate can be explained by the additional stabilization typical for each carbamate: bambuterol by the cation–π interaction between protonated nitrogen and Y440, and by the hydrogen bond between Q197 and the hydroxyl group on the chiral center ; metacarb by two hydrogen bonds between the hydroxyl group on the chiral center with residues H438 and Q197 ; and isocarb by the hydrogen bond between protonated nitrogen and Q197.

molecular modelling; transition state analysis; cholinesterases; carbamates

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