Terpstra_2025_ACS.Chem.Neurosci__

The treatment of Alzheimer's disease by acetylcholinesterase (AChE) and N-methyl-d-aspartate receptor (NMDAR) 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 AChE inhibitor, and memantine, an NMDAR inhibitor, through the addition of amyloid-beta (Abeta)-targeting fragments to create dual-function compounds. The incorporation of the amyloid-targeting fragments successfully produced compounds with affinity for Abeta fibrils, and that can stain amyloid plaques in the brains of 5xFAD mice. The donepezil-based compounds showed significant changes in AChE inhibition compared to donepezil due to the incorporation of the Abeta-targeting fragment and as confirmed by molecular docking studies. The memantine-derived 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-derived compound acts as a prodrug in vivo, releasing memantine within a pharmacologically relevant time frame. Overall, these findings suggest that dual-function compounds may be useful as drug delivery agents that can be metabolized to release an active drug in areas of the brain rich in amyloid plaques and thus could lead to improved treatments for Alzheimer's disease.