Acetylcholinesterase inhibitors in Alzheimer’s disease

McGleenon, B M; Dynan, Kevin B.; Passmore, Anthony Peter

doi:10.1046/j.1365-2125.1999.00026.x

Cited by 326 publications

(223 citation statements)

References 49 publications

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“…After stirring for 30 min, a solution of crude aldehyde in THF (1 mL) was added dropwise, and the resulting mixture was stirred at room temperature for 2 h. The solvent was concentrated under reduced pressure, and to the residual product was added water and extracted three times with CH 2 To a solution of 5 (0.22 g, 0.57 mmol) in THF (5 mL) the Pd-C (0.01 g, 10% Pd-C) was added. The reaction mixture was purged with hydrogen and stirred at room temperature under hydrogen atmosphere for 20 min.…”

Section: General Techniquesmentioning

confidence: 99%

“…A solution of lipoic acid (0.05 g, 0.22 mmol) and PyBOP (0.11 g, 0.22 mmol), in anhydrous CH 2 Cl 2 (3.5 mL), at 0 °C, was stirred for 30 min and then cannulated to a flask containing a solution of 8 (0.11 g, 0.24 mmol), N,N-diisopropylethylamine (0.23 g, 1.76 mmol), in anhydrous CH 2 Cl 2 (4 mL) and the resulting mixture was stirred at room temperature for 20 h. Then, the reaction was quenched by the addition of water and the mixture was extracted four times with CH 2 …”

Section: N-(2-(4-((56-dimethoxymentioning

confidence: 99%

“…1 Patients affected by AD experience progressive cognitive impairment, such as a decline in short-term memory, loss of speech, language and motor coordination. 2,3 AD is pathologically characterized by an extracellular deposition of β-amyloid (Aβ) peptide into senile plaques, intracellular formation of neurofibrillary tangles (NFTs) containing a hyperphosphorylated form of Tau protein, oxidative stress, mitochondrial abnormality, neuroinflammatory processes and neuronal loss, mainly affecting the frontal cortex and hippocampus. 4,5 AD is also characterized by a reduction of acetylcholine (ACh) levels, which is correlated with the cognitive symptoms.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Two Novel Donepezil-Lipoic Acid Hybrids: Synthesis, Anticholinesterase and Antioxidant Activities and Theoretical Studies

Terra¹,

Silva²,

Tramarin³

et al. 2017

J. Braz. Chem. Soc.

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Alzheimer disease (AD) is a complex disease related to multiple pathogenic mechanisms. A strategy to develop effective drugs is based on the so-called multi-target directed ligands (MTDL) by using hybrid compounds. So, in the present study, we have designed and synthesized two hybrids, containing the indanone-piperidine moiety of donepezil, a drug approved for the treatment of AD, and the lipoic acid scaffold, an antioxidant compound endowed with neuroprotective effects. One hybrid was synthesized in four steps with 42% global yield, and the other hybrid in six steps with 19% global yield. The latter hybrid displayed moderate inhibitory activity against human acetylcholinesterase (hAChE) and greater activity against human butyrylcholinesterases (hBuChE). The selectivity for hBuChE was further rationalized by theoretical study. Importantly, the second hybrid showed a good antioxidant activity, exhibiting better ability in scavenging 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals than lipoic acid. Keywords: donepezil-lipoic acid hybrids, Alzheimer disease, multi-target directed ligands IntroductionAlzheimer disease (AD) is the most common cause of dementia in aging population. It was estimated that, in 2010, about 35.6 millions of people suffered from dementia worldwide, and it is expected that this number might triplicate in the next 40 years.1 Patients affected by AD experience progressive cognitive impairment, such as a decline in short-term memory, loss of speech, language and motor coordination. 2,3 AD is pathologically characterized by an extracellular deposition of β-amyloid (Aβ) peptide into senile plaques, intracellular formation of neurofibrillary tangles (NFTs) containing a hyperphosphorylated form of Tau protein, oxidative stress, mitochondrial abnormality, neuroinflammatory processes and neuronal loss, mainly affecting the frontal cortex and hippocampus. 4,5 AD is also characterized by a reduction of acetylcholine (ACh) levels, which is correlated with the cognitive symptoms. 6 The "cholinergic hypothesis", proposed in 1982 by Bartus et al.,7 postulated that the cognitive decline experienced by patients with AD resulted from a deficiency of acetylcholine or cholinergic neurotransmission. In humans, acetylcholine is degraded in the synaptic cleft by two main classes of cholinesterase enzymes: acetyl-(AChE) and butyryl- (BuChE) 8 cholinesterases. Near the amyloid plaques and neurofibrillary tangles, an extensive oxidative stress has been observed 9 which is a result of an altered balance of formation of reactive oxygen species (ROS) versus scavenging activity. 5,10 The production of ROS is also related to calcium homeostasis; the misbalance of calcium influx affects the mitochondrial Terra et al. 739 Vol. 29, No. 4, 2018 enzymes and ROS production is a normal part of the electron transport chain. However, excessive levels of these species damage proteins, lipids and nucleic acids. 9AD is a complex disease related to multiple pathogenic mechanisms involving different molecular targets. All the dru...

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Section: General Techniquesmentioning

confidence: 99%

Section: N-(2-(4-((56-dimethoxymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Two Novel Donepezil-Lipoic Acid Hybrids: Synthesis, Anticholinesterase and Antioxidant Activities and Theoretical Studies

Terra¹,

Silva²,

Tramarin³

et al. 2017

J. Braz. Chem. Soc.

View full text Add to dashboard Cite

show abstract

“…This has resulted in the approval of AChE inhibitors as treatment of mild to moderate AD. However, this is a symptomatic treatment with only 60-70% responders, and it also possesses an array of cholinergic adverse effects (gastrointestinal, cardiovascular and muscle cramps) as a consequence of non-selective increase in cholinergic tonus [65], thus leaving ample room for development of better cholinergic drugs.…”

Section: Drug Development Targeting A4b2 Nachrsmentioning

confidence: 99%

Targeting α4β2 Nicotinic Acetylcholine Receptors in Central Nervous System Disorders: Perspectives on Positive Allosteric Modulation as a Therapeutic Approach

Grupe

Grunnet

Bastlund

et al. 2014

Basic Clin Pharma Tox

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Abstract:The nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels broadly involved in regulating neurotransmission in the central nervous system (CNS) by conducting cation currents through the membrane of neurons. Many different nAChR subtypes exist with each their functional characteristics, expression pattern and pharmacological profile. The focus of the present MiniReview is on the heteromeric a4b2 nAChR, as activity at this subtype contributes to cognitive functioning through interactions with multiple neurotransmitter systems and is implicated in various CNS disorders, for example schizophrenia and Alzheimer's disease. Additionally, the a4b2 nAChR provides an extra layer of molecular complexity by existing in two different stoichiometries determined by the subunit composition. Such findings have founded the rationale that pharmacological modulation of the a4b2 nAChR may be used as a treatment approach in various CNS disorders. As subtype-selective agonists and other cholinergic ligands have only shown limited therapeutic success, the focus of recent drug development endeavours has largely shifted to positive allosteric modulators (PAMs). By potentiating the action of an agonist through binding to an allosteric site, a PAM can enhance cholinergic neurotransmission, thus compensating for compromised neuronal communication in a pathophysiological setting. The pharmacological advantages of PAMs compared to other types of ligands include minimal interference with spatial and temporal aspects of neurotransmission as well as higher subtype selectivity, hypothetically resulting in high clinical efficacy with minimal adverse effects. In this MiniReview, we describe the currently identified compounds, which potentiate the effects of agonists at the a4b2 nAChR. The potential clinical advantages and concerns of PAMs are discussed in the light of the role of a4b2 nAChRs as key regulators of fast synaptic transmission.For decades, the a4b2 subtype of nicotinic acetylcholine (ACh) receptors (nAChRs) has been extensively investigated as a putative drug target in different therapeutic areas. Being widely involved in central neurotransmission as well as implicated in various pathophysiological states, much research has been aimed at developing pharmacological ligands targeting this subtype as a treatment approach in both psychiatric and neurodegenerative diseases [1][2][3][4][5]. The ligand class having received most attention within nAChR drug development aimed at diseases of the central nervous system (CNS) is subtype-selective agonists [1]. However, the success of these efforts must so far be considered limited as the only a4b2 ligands currently approved for medical use are the partial a4b2 nAChR agonists, varenicline and cytisine [6], which are used as smoking cessation aids. This has set off a drug hunt for novel types of modulators targeting the a4b2 nAChR as well as other subtypes of the nAChR family, where the focus has switched from agonists to positive allosteric modulators (PAMs) of the recepto...

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“…Abnormal activity of human acetylcholinesterase (hAChE), the enzyme responsible for hydrolysis of ACh, was attributed to the reduced level of ACh. Treating AD was achieved through inhibiting the anomalous action of AChE [3][4][5][6] by various specific AChE inhibitors [7] such as Donepezil (Aricept®) [8], Tacrine (COGNEX®) [9], and Rivastigmine (EXELON®) [10].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and in silico evaluation of 1N-methyl-1S-methyl-2-nitroethylene (NMSM) derivatives against Alzheimer disease: to understand their interacting mechanism with acetylcholinesterase

et al. 2012

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Anomalous action of human acetylcholinesterase (hAChE) in Alzheimer's disease (AD) was restrained by various AChE inhibitors, of which the specific and potent lead candidate Donepezil is used for treating the disease AD. Besides the specificity, the observed undesirable side effects caused by Donepezil invoked the quest for new lead molecules with the increased potency and specificity for AChE. The present study elucidates the potency of six 1N-methyl-1S-methyl-2-nitroethylene (NMSM) derivatives to form a specific interaction with the peripheral anionic site and catalytic anionic subsite residues of hAChE. The NMSMs were prepared in good yield from 1,1-di(methylsulfanyl)-2-nitroethylene and primary amine (or) amino acid esters. In silico interaction analysis reveals specific and potent interactions between hAChE and selected ligand molecules. The sitespecific interactions formed between these molecules also results in a conformational change in the orientation of active site residues of hAChE, which prevents them from being accessed by beta-amyloid protein (Aβ), which is a causative agent for amyloid plaque formation and acetylcholine (ACh). In silico interaction analysis between the ligand-bounded hAChE with Aß and ACh confirms this observation. The variation in the conformation of hAChE associated with the decreased ability of Aβ and ACh to access the respective functional residues of hAChE induced by the novel NMSMs favors their selection for in vivo analysis to present themselves as new members of hAChE inhibitors.

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Acetylcholinesterase inhibitors in Alzheimer’s disease

Cited by 326 publications

References 49 publications

Two Novel Donepezil-Lipoic Acid Hybrids: Synthesis, Anticholinesterase and Antioxidant Activities and Theoretical Studies

Two Novel Donepezil-Lipoic Acid Hybrids: Synthesis, Anticholinesterase and Antioxidant Activities and Theoretical Studies

Targeting α4β2 Nicotinic Acetylcholine Receptors in Central Nervous System Disorders: Perspectives on Positive Allosteric Modulation as a Therapeutic Approach

Synthesis and in silico evaluation of 1N-methyl-1S-methyl-2-nitroethylene (NMSM) derivatives against Alzheimer disease: to understand their interacting mechanism with acetylcholinesterase

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