engleski

Selectivity of biscarbamates in interaction with human cholinesterases

Acetylcholinesterase and butyrylcholinesterase regulate the concentration of acetylcholine in brain and nerve-muscle cells. A sharp decrease in acetylcholine concentration, is one of the features that characterizies Alzheimer`s disease (AD), manifested by a progressive loss of memory, cognitive function and behavioural changes. Therapy of such and similar forms of dementia is symptomatic with the aim of alleviating symptoms. Restoring the concentration of acetylcholine by inhibiting acetylcholinesterase is the primary treatment for the cognitive deficits. Recent studies have shown that during the progression of AD, AChE activitiy decreases to 10-15% of normal activity, while BChE activity progressively increases and reaches 120% of normal value. Moreover, it has been shown that selective inhibition of BChE in rodents improves cognitive abilities of AD patients. So far, a series of BChE selective inhibitors have been synthesized and tested. The use of carbamates can be promising approach to the development of a new class of cholinesterase inhibitors as drugs for the treatment of neurodegenerative diseases such as AD, which are primarily directed at BChE. 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 BChE 20000 faster than AChE. We used bambuterol as a structural basis for the design and synthesis of new compounds with potential toward the selective inhibition of BChE. We synthesized six alanogues of bambuterol with a modified alkyl chain and the amine part of the molecule. All six analogues have shown the potency to inhibit BChE with inhibition rate (ki) constants up to 10^6 and four of them have shown the same potency to inhibit AChE. Two of them, with cyclopentyl ring in alkyl chain have shown selectivity towards BChE. This two analouges were point out as a structural scaffold for further modifications.

cholinesterases ; selectivity ; biscarbamates

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