Structural Determinants of the Multifunctional Profile of Dual Binding Site Acetylcholinesterase Inhibitors as Anti-Alzheimer Agents

Carles      Galdeano; Elisabet      Viayna; Pau      Arroyo; Axel      Bidon-Chanal; J.      Ramon Blas; Diego      Munoz-Torrero; F.      Javier Luque

doi:10.2174/138161210793176536

Abstract

Dual binding site acetylcholinesterase inhibitors have recently emerged as a new class of anti-Alzheimer agents with potential to positively modify the course of the disease. These compounds exhibit a multifunctional pharmacological profile arising from interaction with several biological targets involved upstream and downstream in the neurodegenerative cascade of Alzheimers disease (AD). The primary target of these compounds is the enzyme acetylcholinesterase (AChE). Interaction of dual binding site AChE inhibitors with AChE results in a potent inhibitory activity of AChE and AChE-induced β-amyloid peptide (Aβ) aggregation. Some dual binding site AChE inhibitors take on added value a significant ability to additionally inhibit the enzymes butyrylcholinesterase and BACE-1, involved in the co-regulation of the hydrolysis of the neurotransmitter acetylcholine and in Aβ formation, respectively. The structural determinants which mediate the interaction of dual binding site AChE inhibitors with these three important enzymes for AD treatment are herein reviewed.

Keywords: Acetylcholinesterase, butyrylcholinesterase, BACE-1, drug-target interactions, structure-based drug design, Anti-Alzheimer agents, Alzheimer's disease, AChE inhibitors, b-amyloid peptide, Dementia, Endoproteinases, Ab vaccine, Ramiprosate, AN1792, Bapineuzumab, CTS-21166, LY450139, MK 0752, E2012, Tacrine, Donepezil, Rivastigmine, Galantamine, Protofibrils, Amylospheroids, Torpedo californica, Thioflavin T fluorescence, Anti-TZ2PA6, Physostigmine analogue, BChE inhibitors, Memoquin