Overview of novel multifunctional agents based on conjugates of γ-carbolines, carbazoles, tetrahydrocarbazoles, phenothiazines, and aminoadamantanes for treatment of Alzheimer's disease

Publication date: Available online 14 May 2019Source: Chemico-Biological InteractionsAuthor(s): Galina F. Makhaeva, Elena F. Shevtsova, Natalia P. Boltneva, Sofya V. Lushchekina, Nadezhda V. Kovaleva, Elena V. Rudakova, Sergey O. Bachurin, Rudy J. RichardsonAbstractAlzheimer's disease (AD) is a multifactorial neurodegenerative process whose effective treatment will require drugs that can act simultaneously on multiple pathogenic targets. Here, we present an overview of our previous multi-target studies of five groups of novel hybrid structures that combine, through spacers, five pharmacophores that have been found promising for AD treatment: γ-carbolines, carbazoles, tetrahydrocarbazoles, phenothiazines, and aminoadamantanes. Biological activity of the compounds was assessed by a battery of assays. These included inhibitory potency against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) as indicators of potential for cognition enhancement and against carboxylesterase (CaE) to exclude unwanted inhibition of this biotransformation pathway. Displacement of propidium from the peripheral anionic site of AChE was determined as a predictor of anti-aggregation activity. Binding to the two sites of the NMDA subtype of the glutamate receptor was conducted as an additional indicator of potential cognition enhancement and neuroprotection. Propensity to protect against mitochondrial triggers of cell death was evaluated by tests of mitochondrial potential and calcium-induced ...
Source: Chemico Biological Interactions - Category: Biochemistry Source Type: research