Heterocyclic inhibitors of AChE acylation and peripheral sites

Notwithstanding the criticism to the so called “ cholinergic hypothesis”, the therapeutic strategies for the treatment of Alzheimer's disease (AD) have been mainly centered on the restoration of cholinergic functionality and, until the last year, the only drugs licensed for the management of AD...

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Published in:Farmaco (Società chimica italiana : 1989) 2005-06, Vol.60 (6), p.465-473
Main Authors: Bolognesi, Maria Laura, Andrisano, Vincenza, Bartolini, Manuela, Cavalli, Andrea, Minarini, Anna, Recanatini, Maurizio, Rosini, Michela, Tumiatti, Vincenzo, Melchiorre, Carlo
Format: Article
Language:English
Subjects:
Acetylcholinesterase
Acetylcholinesterase - chemistry
Acetylcholinesterase - metabolism
Acylation
Alzheimer Disease - drug therapy
Alzheimer Disease - enzymology
Alzheimer's disease
Amyloid-β
Binding Sites
Cholinesterase inhibitors
Cholinesterase Inhibitors - chemistry
Cholinesterase Inhibitors - therapeutic use
Heterocyclic Compounds - chemistry
Heterocyclic Compounds - therapeutic use
Humans
Molecular Structure
Phenylcarbamates - chemistry
Phenylcarbamates - therapeutic use
Physostigmine - chemistry
Physostigmine - therapeutic use
Propidium
Propidium - chemistry
Propidium - therapeutic use
Rivastigmine
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Summary:Notwithstanding the criticism to the so called “ cholinergic hypothesis”, the therapeutic strategies for the treatment of Alzheimer's disease (AD) have been mainly centered on the restoration of cholinergic functionality and, until the last year, the only drugs licensed for the management of AD were the acetycholinesterase (AChE) inhibitors. Target enzyme AChE consists of a narrow gorge with two separate ligand binding sites: an acylation site at the bottom of the gorge containing the catalytic triad and a peripheral site located at the gorge rim, which encompasses binding sites for allosteric ligands. The aim of this short review is to update the knowledge on heterocyclic AChE inhibitors able to interact with the two sites of enzymes, structurally related to the well known inhibitors physostigmine, rivastigmine and propidium. The therapeutic potential of the dual site inhibithors in inhibiting amyloid-ß aggregatrion and deposition is also briefly summarised.
ISSN:0014-827X
1879-0569
DOI:10.1016/j.farmac.2005.03.010