From dual binding site acetylcholinesterase inhibitors to allosteric modulators: A new avenue for disease-modifying drugs in Alzheimer's disease.

Abstract

The lack of an effective treatment for Alzheimer' disease (AD), an increasing prevalence and severe neurodegenerative pathology boost medicinal chemists to look for new drugs. Currently, only acethylcholinesterase (AChE) inhibitors and glutamate antagonist have been approved to the palliative treatment of AD. Although they have a short-term symptomatic benefits, their clinical use have revealed important non-cholinergic functions for AChE such its chaperone role in beta-amyloid toxicity. We propose here the design, synthesis and evaluation of non-toxic dual binding site AChEIs by hybridization of indanone and quinoline heterocyclic scaffolds. Unexpectely, we have found a potent allosteric modulator of AChE able to target cholinergic and non-cholinergic functions by fixing a specific AChE conformation, confirmed by STD-NMR and molecular modeling studies. Furthermore the promising biological data obtained on human neuroblastoma SH-SY5Y cell assays for the new allosteric hybrid 14, led us to propose it as a valuable pharmacological tool for the study of non-cholinergic functions of AChE, and as a new important lead for novel disease modifying agents against AD.

• Authors: Talita P C Chierrito, Susimaire Pedersoli-Mantoani, Carlos Roca, Carlos Requena, Victor Sebastian-Perez, Willian O Castillo, Natalia C S Moreira, Concepción Pérez, Elza T Sakamoto-Hojo, Catarina S Takahashi, Jesús Jiménez-Barbero, F Javier Cañada, Nuria E Campillo, Ana Martinez, Ivone Carvalho
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 139 Pg. 773-791 (Oct 20 2017) ISSN: 1768-3254 [Electronic] France
• PMID: 28863358 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Chemical References

• Cholinesterase Inhibitors
• Acetylcholinesterase

Topics

• Acetylcholinesterase (metabolism)
• Allosteric Regulation (drug effects)
• Alzheimer Disease (drug therapy, pathology)
• Binding Sites (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cholinesterase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Humans
• Models, Molecular
• Molecular Structure
• Structure-Activity Relationship
• Tumor Cells, Cultured