engleski

Adamantane based derivatives as reversible inhibitors of human AChE and BChE

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are two related enzymes responsible to control the level of neurotransmitters. Acetylcholine (ACh) is removed from cholinergic synapse by enzymatic hydrolysis with AChE, which leads to termination of impulse transmission. Both, AChE and BChE, are identified as targets in the treatment of neurodegenerative disorders, such as Alzheimer’s disease (AD). The most used approach in finding new drugs for the treatment of AD is the inhibition of AChE. We synthesized a series of 4- aminoquinoline derivatives of adamantane with different linkers between two subunits, based on the highly active and selective cholinesterase inhibitor with adamantane.1 Compounds were tested as inhibitors of human AChE and BChE, with acetylthiocholine (ATCh) as the substrate for enzyme activity measurements. AChE and BChE activity toward ATCh decreased in the presence of all tested compounds. Inhibition potency of tested compounds expressed as enzyme-inhibitor complex dissociation constant (Ki), ranged from 0.1 to 4.2 μM for AChE and from 0.1 to 7.8 μM for BChE. Changing the length of the linker, structural isomerization and their conformation freedom, we influenced the inhibition potency of compounds, as well as their BChE / AChE selectivity. Increasing of steric demand of molecule resulted in a decrease of inhibitory activity. The compound with n-octyl alkyl chain between quinoline and adamantyl fragments has the lowest Ki values which are approximately 8 and 39 times lower for AChE and BChE respectively than previously tested derivative. [1] Docking simulations showed that adamantyl fragment achieved additional interactions with amino acids residues indicating that adamantane scaffold is important for inhibition of cholinesterase activity, aside from aminoquinoline pharmacophore.

Adamantane ; acetylcholinesterase ; butyrylcholinesterase ; Alzheimer`s disease

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