RUDN chemists suppress overactivity of enzymes that cause Alzheimer’s disease

RUDN University chemists have obtained new azaheterocyclic compounds that inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), regulators of the central nervous system. Increased activity of these enzymes is one of the causes of neurodegenerative diseases. The results were published in Chemico-Biological Interactions.

Neurodegenerative diseases are a large group of severe, irreversible diseases that mainly affect older people. These diseases are characterized by slowly progressive death of nerve cells, leading to a breakdown of connections between parts of the central nervous system, as well as an imbalance in the synthesis and release of the corresponding neurotransmitters. The consequence of this is memory impairment, motor coordination, and a general decrease in a person’s cognitive abilities. The most well-known representatives of this class of diseases are Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, and others.

“One of the most important neurotransmitters is acetylcholine, changes in the metabolism of which lead to severe disruption of brain function. The reason for such changes is the imbalance of the processes of enzymatic regulation of the content of this compound. To destroy acetylcholine molecules, the organism produces two enzymes, AChE and BChE. In a healthy brain, acetylcholine is predominantly hydrolyzed by the first of them, and the second plays an auxiliary role. However, as neurodegenerative diseases progress, acetylcholinesterase activity decreases, while butyrylcholinesterase activity gradually increases. Their combined effect leads to the destruction of a much larger number of acetycholine molecules than necessary. The first generation of drugs to reduce the effects of neurodegenerative diseases were aimed at binding AChE, but both enzymes are currently being considered as therapeutic targets. Our work is aimed at obtaining organic compounds that bind to enzymes and block their activity towards acetylcholine,” Leonid Voskressensky, Doctor of Chemical Sciences, Dean of the Faculty of Physics, Mathematics and Natural Sciences of RUDN University said.

So-called domino reactions were used to synthesize new compounds. This concept includes two or more reactions with the formation of a new bond, occurring under identical conditions, with each subsequent transformation carried out by functional groups resulting from previous reactions. Thus, domino processes are time-separated transformations, reminiscent of the behavior of dominoes, when one of them knocks over the next, which in turn knocks over the next, and so on, so that all the dominoes end up falling. Using this approach, twenty new organic compounds were obtained from the reaction of annelated tetrahydropyridines and azepines with activated alkynes. Their inhibitory activity against acetylcholinesterase and butyrylcholinesterase was studied using combined in vitro and in silico methods.

“The research results show that the synthesized annelated tetrahydroazocines are a promising class of compounds for selective inhibition of BChE with high activity. Of course, we will continue scientific research in this direction,” Leonid Voskressensky, Doctor of Chemical Sciences, Dean of the Faculty of Physics, Mathematics and Natural Sciences of RUDN University said.