title: Heterocyclic inhibitors of AChE acylation and peripheral sites.
abstract: 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-beta aggregatrion and deposition is also briefly summarised.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Via Belmeloro, 6, 40126 Bologna, Italy. marialaura.bolognesi@unibo.it
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Bolognesi
authors.forename: Vincenza
authors.initials: V
authors.lastname: Andrisano
authors.forename: Manuela
authors.initials: M
authors.lastname: Bartolini
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
authors.forename: Anna
authors.initials: A
authors.lastname: Minarini
authors.forename: Maurizio
authors.initials: M
authors.lastname: Recanatini
authors.forename: Michela
authors.initials: M
authors.lastname: Rosini
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Tumiatti
authors.forename: Carlo
authors.initials: C
authors.lastname: Melchiorre
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D000215:Acylation; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D001665:Binding Sites; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D015394:Molecular Structure; D048448:Phenylcarbamates / Q000737:chemistry / Q000627:therapeutic use; D010830:Physostigmine / Q000737:chemistry / Q000627:therapeutic use; D011419:Propidium / Q000737:chemistry / Q000627:therapeutic use; D000068836:Rivastigmine
chemical_list: D002800:Cholinesterase Inhibitors; D006571:Heterocyclic Compounds; D048448:Phenylcarbamates; D011419:Propidium; D010830:Physostigmine; D000110:Acetylcholinesterase; D000068836:Rivastigmine