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2021

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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/173447

Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice

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Recurs relacionat

https://doi.org/10.1021/acs.jmedchem.0c01775

Resum

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.

Matèries

Malalties neuromusculars, Sistema nerviós central, Acetilcolinesterasa

Matèries (anglès)

Neuromuscular diseases, Central nervous system, Acetylcholinesterase

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Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)

Citació

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. Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice. _Journal of Medicinal Chemistry_. 2021. Vol. 64, núm. 1, pàgs. 812-839. [consulta: 20 de gener de 2026]. ISSN: 0022-2623. [Disponible a: https://hdl.handle.net/2445/173447]

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