engleski

Influence of the butyrylcholinesterase gene polymorphism on the inhibition of butyrylcholinesterase by biscarbamates, a potential Alzheimer’s disease drugs

In the middle and late stages of Alzheimer’s disease (AD), the activity of butyrylcholinesterase (BChE), a co-regulator of acetylcholine levels in brain and muscles increases, indicating that selective inhibition of BChE can represent a new pathway in treating AD. The BCHE gene is highly polymorphic and thus far, 66 isoforms of BChE have been discovered. Clinically, the most interesting is atypical BChE because people with it are not able to hydrolyse succinylcholine, a positively charged muscle relaxant and can experience prolonged apnea if it is administered. The efficiacy of any drug that targets BChE activity can be affected by human BCHE gene polymorphisms. We designed and synthesized six biscarbamates with a modified carbamoyl and amine part of the molecule with the aim of determining their BChE inhibition potency toward usual and atypical BChE. The order of magnitude of the carbamylation rate constants ki of all six biscarbamates for usual BChE was 10 6 M-1min-1, which makes these carbamates fast inhibitors for usual BChE. The carbamylation rates of atypical BChE were 400 to 1, 500 time slower compred to usual BChE, proving to the fact that new carbamates are very discriminative to usual BChE. The most discriminative were bisdiethylcarbamates indicating that the carbamylation rate of atypical BChE depends on the substituents on the carbamoyl part of the molecule. In order to evaluate synthesized compounds as potential drugs, their cytotoxicity on human hepatic and neuronal cell was determined. The determined IC50 values showed that adamantyl in the amine part of the molecule decreases carbamate drugability since these carbamates are toxic in concentration ranges used for the inhibition of both types of BChE. Supported by the CFS grants IP-01- 2018-7683, UIP-2017-05-7260 and IMI-IP- 2017-2.

butyrylcholinesterase ; inhibition ; Alzheimer’s disease ; BCHE polymorphism ; cytotoxicity

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