Multi-target design strategies in the context of Alzheimer's disease: acetylcholinesterase inhibition and NMDA receptor antagonism as the driving forces.
In recent years, the multi-target-directed ligand concept has been used to design a variety of molecules hitting different biological targets for Alzheimer's disease. We have sought to combine, in the same molecule, the neuroprotective action of N-methyl-D-aspartate receptor antagonism with the symptomatic relief offered by cholinergic activity through acetylcholinesterase inhibition. This strategy could potentially maintain the positive outcomes of memantine-acetylcholinesterase inhibitor combinations, but with the benefits of a single molecule therapy. Herein, we discuss selected examples of multifunctional compounds, which we rationally designed to simultaneously modulate these targets. We also examine the intertwined relationship between acetylcholinesterase, N-methyl-D-aspartate receptors, and other active players in the neurotoxic cascade.
Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy, michela.rosini@unibo.it.
Michela
M
Rosini
Elena
E
Simoni
Anna
A
Minarini
Carlo
C
Melchiorre
D000110:Acetylcholinesterase / Q000187:drug effects*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D002800:Cholinesterase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D000110:Acetylcholinesterase