Donepezil and Memantine Derivatives for Dual-Function and Prodrug Applications in Alzheimer’s Disease

The treatment of Alzheimer’s disease by acetylcholinesterase and N-methyl-D-aspartate receptor inhibitors is limited by the narrow therapeutic window and adverse side effects of the drugs. This study aims to increase the efficacy and limit the side effects of donepezil, an acetylcholinesterase inhibitor, and memantine, an N-methyl-D-aspartate inhibitor, through the addition of amyloid-targeting fragments to create dual-function compounds. The incorporation of the amyloid-targeting fragments successfully produced compounds with affinity for Aβ42 aggregates and that stain amyloid plaques in the brains of 5xFAD mice. The donepezil-based compounds showed significant changes in acetylcholinesterase inhibition compared to donepezil due to the incorporation of the amyloid-targeting fragment, and as confirmed by molecular docking studies. The memantine-based compound showed good brain uptake in 5xFAD mice but lacked compatibility with NMDAR inhibition, based on in vitro assays and molecular docking. Importantly, the memantine based compound acted as a prodrug in vivo, releasing memantine within a pharmacologically relevant timeframe. Overall, these findings suggest that dual-function compounds may be useful as drug delivery agents that can be metabolized to release an active drug at the site of amyloid plaque deposition, and thus could lead to improved treatments for Alzheimer’s disease.