engleski

Synthesis of biscarbamates as potential selective inhibitors of butyrylcholinesterase

Butyrylcholinesterase (BChE), as well as the structurally homologous acetylcholinesterase (AChE), has been intensively investigated in biomedicine and toxicology. The physiological function of AChE is the hydrolysis of acetylcholine, a nerve impulse transmitter that controls the transmission of nerve impulses in the cholinergic synapses of the central and peripheral nervous system, thus maintaining the homeostasis of the organism. Although BChE has no essential physiological role, it is involved in the metabolism of a variety of drugs and xenobiotics acting as an endogenous bioscavenger. Furthermore, the treatment of neurodegenerative diseases such as Alzheimer's disease (AD), myasthenia gravis and Parkinson's disease is symptomatic and is based on the inhibition of cholinesterase. Most of the drugs currently used are non-selective cholinesterase inhibitors or selectively inhibit AChE, which is done with donepezil. Recent studies have shown that during the progression of Alzheimer's disease (AD), AChE activity decreases to 10-15% of normal AChE activity, while BChE activity progressively increases and reaches 120% of the normal value. It has been shown that selective inhibition of BChE in rodents improves cognitive abilities and decreases the concentration of neurotoxic plaques found in the brain of AD patients. So far, a series of tacrine and phenotiazine derivatives have been synthesized and tested. Promising results were shown for carbamate cymserine, however its development as a drug in AD treatment was halted because of the formation of toxic metabolites. The biscarbamate ester bambuterol, a terbutaline prodrug used in the treatment of asthma, has been shown to be a highly selective BChE inhibitor that inhibits human BChE 20000 times faster than erythrocyte AChE. We synthesized 18 analogues of bambuterol with a modified alkyl chain and the amine part of the molecule. From an evaluation of their potential to inhibit both human cholinesterases, several BChE selective inhibitors will be selected for further analysis. The structural characteristics of this class of compounds that determine the selectivity to BChE will also be determined.

AChE ; BChE ; selectivity ; bambuterol ; biscarbamates

nije evidentirano