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; Coquelle, Nicolas; Cieslikiewicz-Bouet, Monika; Cisternas, Pedro; Oliva, Carolina A.; Sanchez-Lopez, Elena; Ettcheto, Miren; Bartolini, Manuela; De Simone, Angela; Ricchini, Mattia; Rendina, Marisa; Pons, Megane; Firuzi, Omidreza; Perez, Belen; Saso, Luciano; Andrisano, Vincenza; Nachon, Florian; Brazzolotto, Xavier; Luisa Garcia, Maria; Camins, Antoni

doi:10.1021/acs.jmedchem.0c01775

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

[1];

Coquelle, Nicolas

[2];

Cieslikiewicz-Bouet, Monika

[2];

Cisternas, Pedro

[3];

Oliva, Carolina A.

[3];

Sanchez-Lopez, Elena

[4];

Ettcheto, Miren

[5];

Bartolini, Manuela

[6];

De Simone, Angela

[7];

Ricchini, Mattia

[1];

Rendina, Marisa

[1];

Pons, Megane

[2];

Firuzi, Omidreza

[8];

Perez, Belen

[9];

Saso, Luciano

[10];

Andrisano, Vincenza

[6];

Nachon, Florian

[11];

Brazzolotto, Xavier

[11];

Luisa Garcia, Maria

[4];

Camins, Antoni

[5];

Silman, Israel

[12];

Jean, Ludovic

[2];

Inestrosa, Nibaldo C.

[13];

Colletier, Jacques-Philippe

[2];

Renard, Pierre-Yves

[2];

Munoz-Torrero, Diego

[1]

¹
Consejo Superior de Investigaciones Cientificas (CSIC)
²
Centre National de la Recherche Scientifique (CNRS)
³
Pontificia Universidad Catolica de Chile
⁴
University of Barcelona
⁵
Inst Hlth Carlos III
⁶
University of Bologna
⁷
University of Turin
⁸
Shiraz University of Medical Science
⁹
Autonomous University of Barcelona
¹⁰
Sapienza University Rome
¹¹
Inst Rech Biomed Armees
¹²
Weizmann Institute of Science
¹³
Universidad de Magallanes

DOI

10.1021/acs.jmedchem.0c01775

Date Issued

2021-1-14

Type

Artículo

Journal

Journal of Medicinal Chemistry

ISSN

0022-2623

1520-4804

Open Access

green

Volume

64

Start page

812

End page

839

Links

https://arca.umag.cl/handle/123456789/13991

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.

Butyrylcholinesterase...

Cholinesterase

Name

document.pdf

Type

Main Article

Size

4.1 MB

Format

Adobe PDF

Checksum

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