engleski

Selectivity of biscarbamtes in interaction with human cholinesterases

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) regulate the concentration of acetylcholine in brain and nerve-muscle cells. A sharp decrease in acetylcholine concentration is a feature that characterizes Alzheimer`s disease (AD), manifested by a progressive loss of memory. Therapy of such and similar forms of dementia is symptomatic with the aim of alleviating symptoms. Restoring the concentration of acetylcholine by inhibiting AChE is the primary treatment for cognitive deficits. Recent studies have shown that, during the progression of AD, AChE activitiy decreases to 15% of normal activity, while BChE activity progressively increases and reaches 120% of normal value. Also, it has been shown that selective inhibition of BChE improves cognitive abilities in rodents. 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 20, 000 times faster than AChE. We used bambuterol as a structural base for the design and synthesis of new compounds with potential toward the selective inhibition of BChE. We synthesized six analogues of bambuterol with a modified alkyl chain and the amine part of the molecule, and tested their ability to inhibit human cholinesterases. All six analogues have shown to be potent BChE inhibitors with inhibition rate constants (ki) in the same order of magnitude as that for bambuterol, up to 4.5·106 M-1 min -1. Four compounds were equally potent inhibitors of AChE showing no selectivity toward BChE regarding AChE. Compounds with a cyclopentyl ring in the alkyl part of the carbamates, regardless of the substituent on the amino part of the molecule, have shown about a 1000 times higher selectivity towards BChE. Therefore, it seems the substituent at the alkyl part of carbamates is the most important for their selectivity in the interaction with human cholinesterases. Moreover, these two carbamates could present a structural scaffold for further modifications with the aim of drug development for the treatment of neurodegenerative diseases, such as AD, based on selective cholinesterase inhibition.

Acetylcholinesterase ; butyrylcholinesterase ; selectivity ; bambuterol ; biscarbamates

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