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Title: Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice
Author: Viayna, Elisabet
Coquelle, Nicolas
Cieslikiewicz-Bouet, Monika
Cisternas, Pedro
Oliva, Carolina
Sánchez-López, E. (Elena)
Ettcheto Arriola, Miren
Bartolini, Manuela
De Simone, Angela
Ricchini, Mattia
Rendina, Marisa
Pons, Mégane
Firuzi, Omidreza
Pérez, Belén
Saso, Luciano
Andrisano, Vincenza
Nachon, Florian
Brazzolotto, Xavier
García, Maria Luisa
Camins Espuny, Antoni
Silman, Israel
Jean, Ludovic
Inestrosa, Nibaldo C.
Colletier, Jacques-Philippe
Renard, Pierre-Yves
Muñoz-Torrero López-Ibarra, Diego
Keywords: Malalties neuromusculars
Sistema nerviós central
Neuromuscular diseases
Central nervous system
Issue Date: 2021
Publisher: American Chemical Society
Abstract: 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 C57BL6 mice, with one compound (5i) displaying better brain/plasma ratio than donepezil. Chronic treatment of 10 month-old APP/PS1 mice with 5i (2 mg/kg, ip, 3 times per week, 4 weeks) rescued learning and memory impairments, as measured by 3 different behavioral tests, delayed the Alzheimer-like pathology progression, as suggested by a significantly reduced Aβ42/Aβ40 ratio in hippocampus, improved basal synaptic efficacy, and significantly reduced hippocampal oxidative stress and neuroinflammation. Compound 5i emerges as an interesting anti-Alzheimer lead with beneficial effects on cognitive symptoms and on some underlying disease mechanisms.
Note: Versió postprint del document publicat a:
It is part of: Journal of Medicinal Chemistry, 2021, vol. 64, num. 1, p. 812-839
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ISSN: 0022-2623
Appears in Collections:Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)

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