Donepezil Hydrochloride (E2020) and Other Acetylcholinesterase Inhibitors

Sugimoto, Hachiro; Yamanishi, Yoshihiro; Iimura, Youichi; Kawakami, Yoshiyuki

doi:10.2174/0929867003375191

Cited by 281 publications

(174 citation statements)

References 71 publications

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“…This result was confirmed by the mixed type competitive AChE inhibitor profile of donecopride (Fig. 4) and accounts for its potential inhibitory effect against AChE-induced Aβ aggregation (33).…”

Section: Rs67333 Is a Submicromolar (H)achesupporting

confidence: 72%

Design of donecopride, a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer's disease treatment

Lecoutey

Hédou

Freret

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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RS67333 is a partial serotonin subtype 4 receptor (5-HT 4 R) agonist that has been widely studied for its procognitive effect. More recently, it has been shown that its ability to promote the nonamyloidogenic cleavage of the precursor of the neurotoxic amyloid-β peptide leads to the secretion of the neurotrophic protein sAPPα. This effect has generated great interest in RS67333 as a potential treatment for Alzheimer's disease (AD). We show herein that RS67333 is also a submicromolar acetylcholinesterase (AChE) inhibitor and therefore, could contribute, through this effect, to the restoration of the cholinergic neurotransmission that becomes altered in AD. We planned to pharmacomodulate RS67333 to enhance its AChE inhibitory activity to take advantage of this pleiotropic pharmacological profile in the design of a novel multitargetdirected ligand that is able to exert not only a symptomatic but also, a disease-modifying effect against AD. These efforts allowed us to select donecopride as a valuable dual (h)5-HT 4 R partial agonist (K i = 10.4 nM; 48.3% of control agonist response)/(h)AChEI (IC 50 = 16 nM) that further promotes sAPPα release (EC 50 = 11.3 nM). Donecopride, as a druggable lead, was assessed for its in vivo procognitive effects (0.1, 0.3, 1, and 3 mg/kg) with an improvement of memory performances observed at 0.3 and 1 mg/kg on the object recognition test. On the basis of these in vitro and in vivo activities, donecopride seems to be a promising drug candidate for AD treatment.

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Section: Rs67333 Is a Submicromolar (H)achesupporting

confidence: 72%

Design of donecopride, a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer's disease treatment

Lecoutey

Hédou

Freret

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…[3][4][5][6][7][8][9][10] Donepezil, galantamine and tacrine are acetylcholinesterase inhibitors (AChEI) that have been developed for the treatment of AD under the presumption that increasing cholinergic transmission through inhibition of acetylcholinesterase will enhance cognitive function. 11,12) Donepezil is a potent and reversible acetylcholinesterase inhibitor that shows moderate improvement of cognitive function with minimal side effects 13) (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Roles of Nicotinic Receptors in Acetylcholinesterase Inhibitor-Induced Neuroprotection and Nicotinic Receptor Up-Regulation

Takada‐Takatori

Kume

Izumi

et al. 2009

Biological & Pharmaceutical Bulletin

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Protection of neurons from neuronal damage and cell death in neurodegenerative disease is a major challenge in neuroscience research. Donepezil, galantamine and tacrine are acetylcholinesterase inhibitors used for the treatment of Alzheimer's disease, and were believed to be symptomatic drugs whose therapeutic effects are achieved by slowing the hydrolysis of acetylcholine at synaptic termini. However, recent accumulated evidence strongly suggests that these acetylcholinesterase inhibitors also possess neuroprotective properties whose mechanism is independent of acetylcholinesterase inhibition. We have shown that acetylcholinesterase inhibitors protect neurons from glutamate-induced neurotoxicity in the primary culture of rat cortical neurons. It was also found that acetylcholinesterase inhibitor treatment induces up-regulation of nicotinic receptor expression levels, a property which may also have some bearing on their therapeutic effects. We next showed that a a4 and a a7-nicotinic receptors play important roles in acetylcholinesterase inhibitor-induced neuroprotection and nicotinic receptor up-regulation. Our results also demonstrate the important roles of the phosphatidylinositol 3-kinase pathway downstream of nicotinic receptors in protecting neurons from death and up-regulating nicotinic receptors. This review summarizes recent findings on the roles of the nicotinic receptor in acetylcholinesterase inhibitor-induced neuroprotection and nicotinic receptor up-regulation.

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“…This result indicate the beneficial effect of Vitamin A in cognition enhancing effect and is currently being studied for its beneficial effect on Alzheimer's disease. 17 Also, the presence of Glucosinolate in higher concentration in Brassica campestris species can be responsible for its cognition enhancement activity. 18 While compounds like physcion from Cassia tora leaves has GLIDE score of -10.2 and bond strength of -2.22 Å (Figure 3 and 4) showed tight binding between ligand and AChE, the flavonoids like quercetin, sigmasterol, β stigmasterol showed comparable GLIDE score but weak bonding with AChE proteins when compared with Aricept-AChE complex.…”

Section: Resultsmentioning

confidence: 99%

Molecular Docking Study of Cassia tora, Brassica campestris and Calotropis procera as Acetylcholinesterase Inhibitor.

H¹,

D²,

R³

et al. 2016

IJPER

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Introduction: Acetylcholinesterase inhibitor is the only standard and FDA approved drug therapy for Alzheimer's disease and its associated disorders. Numerous plants and their phytoconstiuents are being reported to inhibit acetylcholinesterase. To get insight of the intermolecular interactions, the molecular docking studies are performed at active site of acetylcholinesterase enzyme. Aim: In this study, an attempt is made for identification of potential ligands from selected 30 compounds which are reported to be present in Cassia tora, Brassica campestris and Calotropis procera, targeted against acetylcholinesterase using molecular modelling and docking studies. Results: The relative binding affinity of the compounds towards AChE was selected on the basis of docking score, GLIDE score and interaction patterns.Several compounds showed stronghydrogen bonding to several important amino acid residues andtheir hydrophobic interactions could also explain their potency to inhibit acetylcholinesterase. These compoundsbelong to different classes like flavonoids, vitamin, cardenolides and etc. Some of these compounds have been reported for their beneficial effect on dementia related disorders, while remaining are suggested to be potential acetylcholinesterase inhibitors. Conclusion: Hence, this study provides evidencefor consideration of valuable ligand molecule as potential acetylcholinesterase inhibitorandfurther in vitro and in vivo investigations may prove its therapeutic potential

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Donepezil Hydrochloride (E2020) and Other Acetylcholinesterase Inhibitors

Cited by 281 publications

References 71 publications

Design of donecopride, a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer's disease treatment

Design of donecopride, a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer's disease treatment

Roles of Nicotinic Receptors in Acetylcholinesterase Inhibitor-Induced Neuroprotection and Nicotinic Receptor Up-Regulation

Molecular Docking Study of Cassia tora, Brassica campestris and Calotropis procera as Acetylcholinesterase Inhibitor.

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