Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice
Viayna, Elisabet
Consejo Superior de Investigaciones Cientificas (CSIC)
Coquelle, Nicolas
Centre National de la Recherche Scientifique (CNRS)
Cieslikiewicz-Bouet, Monika
Centre National de la Recherche Scientifique (CNRS)
Cisternas, Pedro
Pontificia Universidad Catolica de Chile
Oliva, Carolina A.
Pontificia Universidad Catolica de Chile
Sanchez-Lopez, Elena
University of Barcelona
Ettcheto, Miren
Inst Hlth Carlos III
Bartolini, Manuela
University of Bologna
De Simone, Angela
University of Turin
Ricchini, Mattia
Consejo Superior de Investigaciones Cientificas (CSIC)
Rendina, Marisa
Consejo Superior de Investigaciones Cientificas (CSIC)
Pons, Megane
Centre National de la Recherche Scientifique (CNRS)
Firuzi, Omidreza
Shiraz University of Medical Science
Perez, Belen
Autonomous University of Barcelona
Saso, Luciano
Sapienza University Rome
Andrisano, Vincenza
University of Bologna
Nachon, Florian
Inst Rech Biomed Armees
Brazzolotto, Xavier
Inst Rech Biomed Armees
Luisa Garcia, Maria
University of Barcelona
Camins, Antoni
Inst Hlth Carlos III
Silman, Israel
Weizmann Institute of Science
Jean, Ludovic
Centre National de la Recherche Scientifique (CNRS)
Colletier, Jacques-Philippe
Centre National de la Recherche Scientifique (CNRS)
Renard, Pierre-Yves
Centre National de la Recherche Scientifique (CNRS)
Munoz-Torrero, Diego
Consejo Superior de Investigaciones Cientificas (CSIC)
Journal
Journal of Medicinal Chemistry
ISSN
0022-2623
1520-4804
Open Access
green
Volume
64
Start page
812
End page
839
The combination of the scaffolds of the cholinesterase inhibitor huprine Y and the antioxidant capsaicin results in compounds with nanomolar potencies toward human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) that retain or improve the antioxidant properties of capsaicin. Crystal structures of their complexes with AChE and BChE revealed the molecular basis for their high potency. Brain penetration was confirmed by biodistribution studies in CS7BL6 mice, with one compound (Si) displaying better brain/plasma ratio than donepezil. Chronic treatment of 10 month-old APP/PS1 mice with 5i (2 mg/kg, i.p., 3 times per week, 4 weeks) rescued learning and memory impairments, as measured by three different behavioral tests, delayed the Alzheimer-like pathology progression, as suggested by a significantly reduced A beta 42/A beta 40 ratio in the hippocampus, improved basal synaptic efficacy, and significantly reduced hippocampal oxidative stress and neuroinflammation. Compound Si emerges as an interesting anti-Alzheimer lead with beneficial effects on cognitive symptoms and on some underlying disease mechanisms.
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Type
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