Is there a rationale for the use of acetylcholinesterase inhibitors in the therapy of Alzheimer's disease?

Benzi, G.; Moretti, Antonio

doi:10.1016/s0014-2999(98)00093-4

Cited by 147 publications

(81 citation statements)

References 117 publications

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“…The results in Table 1 Likewise, although it is not fully established that the selectivity in inhibiting AChE vs BChE results in low peripheral cholinergic effects in AD patients, 32 it is worth noting that these compounds, particularly rac-19, (-)-20, (-)-30, and rac-31, are 438-871-fold more active inhibiting human AChE than human BChE, being much more selective than tacrine ( Table 1).…”

Section: Scheme 1 Synthetic Procedures For the Preparation Of Huprinesmentioning

confidence: 99%

New Tacrine−Huperzine A Hybrids (Huprines): Highly Potent Tight-Binding Acetylcholinesterase Inhibitors of Interest for the Treatment of Alzheimer's Disease

et al. 2000

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Several new 12-amino-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinoline derivatives (tacrine-huperzine A hybrids, huprines) have been synthesized and tested as acetylcholinesterase (AChE) inhibitors. All of the new compounds contain either a methyl or ethyl group at position 9 and one or two (chloro, fluoro, or methyl) substituents at positions 1, 2, or 3. Among the monosubstituted derivatives, the more active are those substituted at position 3, their activity following the order 3-chloro > 3-fluoro > 3-methyl > 3-hydrogen. For the 1,3-difluoro and 1,3-dimethyl derivatives, the effect of the substituents is roughly additive. No significant differences were observed for the inhibitory activity of 9-methyl vs 9-ethyl derivatives monoor disubstituted at positions 1 and/or 3. The levorotatory enantiomers of these hybrid compounds are much more active (eutomers) than the dextrorotatory forms (distomers) as AChE inhibitors. Compounds rac-20, (-)-20, rac-26, (-)-26, rac-30, (-)-30, and rac-31 showed human AChE inhibitory activities up to 28.5-fold higher than for the corresponding bovine enzyme. Also, rac-19, (-)-20, (-)-30, and rac-31 were very selective for human AChE vs butyrylcholinesterase (BChE), the AChE inhibitory activities being 438-871-fold higher than for BChE. Several hybrid compounds, specially (-)-20 and (-)-30, exhibited tight-binding character, showing higher activity after incubation of the enzyme with the inhibitor than without incubation, though the reversible nature of the enzyme-inhibitor interaction was demonstrated by dialysis. The results of the ex vivo experiments also supported the tight-binding character of compounds (-)-20 and (-)-30 and showed their ability to cross the blood-brain barrier. Molecular modeling simulations of the AChE-inhibitor complex provided a basis to explain the differences in inhibitory activity of these compounds.

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Section: Scheme 1 Synthetic Procedures For the Preparation Of Huprinesmentioning

confidence: 99%

New Tacrine−Huperzine A Hybrids (Huprines): Highly Potent Tight-Binding Acetylcholinesterase Inhibitors of Interest for the Treatment of Alzheimer's Disease

et al. 2000

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“…The organic layer was concentrated to give compound 33 (1.52 g 99%) as brown oil; R f = 0. 6 Pharmacology. Inhibition of EeAChE and eqBuChE.…”

Section: ■ Methodsmentioning

confidence: 99%

“…5 For a while the treatment with AChEIs was reported to produce only symptomatic improvement, having no effect in the course of the disease. 6 However, other studies indicated that AChE interacts with Aβ by an hydrophobic environment close to the PAS, thus promoting Aβ fibril formation. 7,8 Moreover, AChE-Aβ complexes increase Aβ-dependent neurotoxicity.…”

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confidence: 98%

Synthesis, Pharmacological Assessment, and Molecular Modeling of Acetylcholinesterase/Butyrylcholinesterase Inhibitors: Effect against Amyloid-β-Induced Neurotoxicity

Silva

Chioua

Samadi

et al. 2013

ACS Chem. Neurosci.

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ABSTRACT:The synthesis, molecular modeling, and pharmacological analysis of phenoxyalkylamino-4-phenylnicotinates (2−7), phenoxyalkoxybenzylidenemalononitriles (12, 13), pyridonepezils (14−18), and quinolinodonepezils (19−21) are described. Pyridonepezils 15−18 were found to be selective and moderately potent regarding the inhibition of hAChE, whereas quinolinodonepezils 19−21 were found to be poor inhibitors of hAChE. The most potent and selective hAChE inhibitor was ethyl 6-(4-(1-benzylpiperidin-4-yl)butylamino)-5-cyano-2-methyl-4-phenylnicotinate (18) [IC 50 (hAChE) = 0.25 ± 0.02 μM]. Pyridonepezils 15−18 and quinolinodonepezils 20−21 are more potent selective inhibitors of EeAChE than hAChE. The most potent and selective EeAChE inhibitor was ethyl 6-(2-(1-benzylpiperidin-4-yl)ethylamino)-5-cyano-2-methyl-4-phenylnicotinate (16) [IC 50 (EeAChE) = 0.0167 ± 0.0002 μM], which exhibits the same inhibitory potency as donepezil against hAChE. Compounds 2, 7, 13, 17, 18, 35, and 36 significantly prevented the decrease in cell viability caused by Aβ 1−42 . All compounds were effective in preventing the enhancement of AChE activity induced by Aβ 1−42 . Compounds 2−7 caused a significant reduction whereas pyridonepezils 17 and 18, and compound 16 also showed some activity . The pyrazolo [3,4-b]quinolines 36 and 38 also prevented the upregulation of AChE induced by Aβ 1−42 . Compounds 2, 7, 12, 13, 17, 18, and 36 may act as antagonists of voltage sensitive calcium channels, since they significantly prevented the Ca 2+ influx evoked by KCl depolarization. Docking studies show that compounds 16 and 18 adopted different orientations and conformations inside the active-site gorges of hAChE and hBuChE. The structural and energetic features of the 16-AChE and 18-AChE complexes compared to the 16-BuChE and 18-BuChE complexes account for a higher affinity of the ligand toward AChE. The present data indicate that compounds 2, 7, 17, 18, and 36 may represent attractive multipotent molecules for the potential treatment of Alzheimer's disease.

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“…It had been postulated that the second and third generation cholinesterase inhibitors clinically used in the treatment of Alzheimer's Disease (Tacrine, Donepezil, rivastigmine, Galanthamine) inhibit AChE in a therapeutic efficacy window at a rate of 30-60 % [22]. For this reason patients taking medications to treat Alzheimer's disease were excluded from the study.…”

Section: Study Population and Designmentioning

confidence: 99%

The Red Blood Cell Acetylcholinesterase Levels of Depressive Patients with Suicidal Behavior in an Agricultural Area

et al. 2016

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Long-term exposure to organophosphate pesticides (OPs) without acute poisoning can lead to various OPs. Environmental exposure to organophosphate pesticides may be associated with depression and suicide attempts in a population living in a rural agricultural area. Patients (n = 149) suffering from major depressive disorder (with and without attempted suicide) and a control group of healthy individuals (n = 64) who had been living in the same rural district for at least 1 year were selected. Red blood cell acetylcholine esterase (RBC-AChE) activity was examined as the basis of evaluating the degree of chronic environmental exposure to OPs residues. There were negative association between RBC-AChE activity levels and suicide attempts, the number of past suicide attempts and hopelessness levels in the depressive patients.The results of the study may support the idea that environmental exposure to OPs may be associated with mental health in individuals living in agricultural districts who are not farmers or working in occupations with access to OPs.

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Is there a rationale for the use of acetylcholinesterase inhibitors in the therapy of Alzheimer's disease?

Cited by 147 publications

References 117 publications

New Tacrine−Huperzine A Hybrids (Huprines): Highly Potent Tight-Binding Acetylcholinesterase Inhibitors of Interest for the Treatment of Alzheimer's Disease

New Tacrine−Huperzine A Hybrids (Huprines): Highly Potent Tight-Binding Acetylcholinesterase Inhibitors of Interest for the Treatment of Alzheimer's Disease

Synthesis, Pharmacological Assessment, and Molecular Modeling of Acetylcholinesterase/Butyrylcholinesterase Inhibitors: Effect against Amyloid-β-Induced Neurotoxicity

The Red Blood Cell Acetylcholinesterase Levels of Depressive Patients with Suicidal Behavior in an Agricultural Area

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