Alzheimer's disease is a multifunctional neurodegenerative disease featuring a decline in cholinergic transmission, as well as dysfunction of the noradrenergic system activity in the brain. The disease is characterised by increased butyrylcholinesterase (BChE) activity, which becomes the predominant brain cholinesterase. Its enlarged active site allows the rational design of selective inhibitors. Oligomers of amyloid β bind to α2A adrenergic receptors (α2AAR), leading to GSK3β activation and tau hyperphosphorylation. Multifunctional compounds that act simultaneously on both neurotransmitter systems have a great potential for a more effective treatment that could even slow down the neurodegenerative processes in the brain.
In the master's thesis, 10 compounds were designed and synthesized to achieve both human hBChE inhibition and α2AAR antagonism. The starting point was atipamezole (a known selective α2AR antagonist). Using N-acylation, we have introduced a carbamate group, which is crucial for the inhibition of cholinesterases, in its structure.
Only the carbamates (7, 8, 11–13 and 16) covalently bound to and inhibited hBChE. All carbamates, except compound 11, inhibited the enzyme at nanomolar concentrations, and were more selective for hBChE over acetylcholinesterase. The compound with the highest potential for further optimisation is compound 16, which selectively inhibits hBChE with an IC50 value of 2.39 nM.
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