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

Elisabet Viayna, Nicolas Coquelle, Monika Cieslikiewicz-Bouet, Pedro Cisternas, Carolina A. Oliva, Elena Sánchez-López, Miren Ettcheto, Manuela Bartolini, Angela De Simone, Mattia Ricchini, Marisa Rendina, Mégane Pons, Omidreza Firuzi, Belén Pérez, Luciano Saso, Vincenza Andrisano, Florian Nachon, Xavier Brazzolotto, Maria Luisa García, Antoni CaminsIsrael Silman, Ludovic Jean, Nibaldo C. Inestrosa, Jacques Philippe Colletier, Pierre Yves Renard, Diego Muñoz-Torrero*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)812-839
Number of pages28
JournalJournal of Medicinal Chemistry
Volume64
Issue number1
DOIs
Publication statusPublished - 28 Dec 2020

Keywords

  • TARGET-DIRECTED LIGANDS
  • BETA-AMYLOID PLAQUES
  • HUPRINE DERIVATIVES
  • OXIDATIVE STRESS
  • ANTICHOLINESTERASE AGENTS
  • COGNITIVE PERFORMANCE
  • RATIONAL DESIGN
  • MOUSE MODEL
  • DISEASE
  • CAPSAICIN

Fingerprint

Dive into the research topics of 'Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice'. Together they form a unique fingerprint.

Cite this