Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 1, Pages 812-839Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c01775
Keywords
-
Categories
Funding
- Ministerio de Ciencia, Innovacion y Universidades (MCIU)
- Agencia Estatal de Investigacion (AEI)
- FEDER [SAF2017-82771-R, SAF2014-57094-R]
- Generalitat de Catalunya (GC) [2017SGR106]
- Agence Nationale de la Recherche (ANR) [ANR-12-BS07-0008-01]
- France Alzheimer Foundation [FA-AAP-2013-65-101349]
- Italian Ministry of Education, University and Research - MIUR
- Basal Center of Excellence in Aging and Regeneration (CONICYT) [AFB 170005]
- FONDECYT [11160651]
- MIADES [T010131, T010132]
- Sociedad Quimica y Minera de Chile (SQM)
- GC
- ANR
- Lifelong Learning Programme/Erasmus
- Leonardo da Vinci Project Unipharma-Graduates 5
- Shiraz University of Medical Sciences
Ask authors/readers for more resources
By combining the scaffolds of the cholinesterase inhibitor huprine Y and the antioxidant capsaicin, compounds with nanomolar potencies towards AChE and BChE were created, demonstrating potential therapeutic effects for Alzheimer's disease.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available