Competitive Inhibitor Of Acetylcholinesterase Research Articles

Therapeutic and medicinal effects of snowdrop (Galanthus spp.) in Alzheimer's disease: A review.

Genus Galanthus (Amaryllidaceae) is an early spring flowering bulbous plant. Galanthus species contain alkaloids that have shown pharmacological activity. Galanthamine is an alkaloid that was extracted from Galanthus and other Amaryllidaceae. Owing to its acetylcholinesterase (AChE) inhibitory activity, galanthamine is used and marketed to treat Alzheimer's disease (AD). The aim of the present study, while introducing the botanical and pharmacological characteristics and various aspects of the medicinal plant Galanthus, is to emphasize the effect of this plant in the treatment of AD. In this web-based study in 2021, articles indexed in scientific databases in English language, including ISI Web of Knowledge, PubMed, Scopus, MedLib, Medknow, SID, ISC, and also articles and e-books published in Springer, Elsevier, John Wiley and Sons, and Taylor and Francis were evaluated from 1990 to 2021, using the following keywords: "Galanthus" "galanthamine," "Alzheimer's disease." Amaryllidaceae-type alkaloids possess an anticholinesterase activity. The most studied Galanthus alkaloid, galanthamine, is a long-acting, selective, reversible, competitive inhibitor of AChE and an allosteric modulator of the neuronal nicotinic receptor for acetylcholine (ACh). Owing to its AChE inhibitory activity, galanthamine is used to treat certain stages of AD. Galantamine can act as a parasympathomimetic agent, especially as a reversible cholinesterase inhibitor. Galantamine is not structurally associated with other AChE inhibitors. Hence, its proposed mechanism of action involves the reversible inhibition of AChE, preventing hydrolysis of ACh that results in an increased concentration of ACh at cholinergic synapses.

Biodriven investigation of the wild edible mushroom Pleurotus eryngii revealing unique properties as functional food

• Pleurotus eryngii extract activate the Nrf2 and enhance the antioxidant activity. • N -acetyl tryptamine found in Pleurotus eryngii inhibits acetylcholinesterase. • Pleurotus eryngii contain high level of Zinc and other essential trace elements. • Pleurotus eryngii extract acts on several genes expression, suggesting potential protection against life threatening diseases. Pleurotus eryngii ( P. eryngii ) is largely represented among consumed mushrooms. We conducted an investigation dealing with its antioxidant potential, the presence of essential trace elements and its contribution to the management of brain-related disorders. A bio-guided extraction revealed that one extract was highly effective on activation of the nuclear factor Nrf2, the regulator of the cellular resistance to oxidants. Its analysis revealed the presence of N -acetyltryptamine (NAT), a precursor of the neurotransmitters, melatonin and serotonin. Both extract and NAT, were found as competitive inhibitors of acetylcholinesterase. The essential trace elements analyses showed the presence of high amounts of zinc. RNA-seq technology confirmed upregulates expression of Nrf2 on HepG2 cells and revealed key genes involved in anticholesterolemic, antioxidant effects, cancer and brain disorders. Our study achieved a comprehensive strengthening of the nutritional health-benefit properties of P. eryngii largely used in folk medicines and open perspectives for investigation in food and medicine.

Six-step total syntheses of (−)-galanthamine and (−)-

The Amaryllidaceae alkaloid (−)-galanthamine (1) is a reversible, competitive acetylcholinesterase inhibitor deployed clinically to treat the dementia associated with Alzheimer’s disease. Here, we describe a six-step synthesis of this natural product from simple, readily accessible starting materials. Enantioselective 1,2-reduction, Mitsunobu coupling, Heck cyclization and diastereoselective allylic oxidation reactions are used in our approach, which provides the shortest synthetic route to compound 1 reported to date. A simple modification to the closing stages of the sequence allows equally facile access to (−)-N-norgalanthamine (2), a compound with a range of distinctive biological properties. The concise and operationally simple synthetic protocols reported here could obviate the need to manipulate naturally sourced galanthamine in the pursuit of analogues required for pharmacological studies.

In Vitro and In Silico Kinetic Studies of Patented 1,7-diEthyl and 1,7-diMethyl Aminoalkanol Derivatives as New Inhibitors of Acetylcholinesterase.

Two aminoalkanol derivatives of 1,7-diEthyl-8,9-diphenyl-4azatricyclo (5.2.1.02.6) dec-8-ene-3,5,10-trione and two derivatives of 1,7-diMethyl-8,9-diphenyl-4-azatricyclo (5.2.1.02.6) dec-8-ene-3,5,10-trione were evaluated in vitro for their inhibition efficacy of acetylcholinesterase. The Km, Vmax, slope angles of Lineweaver–Burk plots, Ki and IC50 values showed that all four aminoalkanol derivatives are competitive inhibitors of acetylcholinesterase whose inhibitory potency depends, to a varying extent, on the nature of the four different substituents present in the main compound structure. Studies have shown that the most potent acetylcholinesterase inhibitors are derivatives containing isopropylamine and/or methyl substituents in their structure. In contrast, dimethylamine and/or ethyl substituents seem to have a weaker, albeit visible, effect on the inhibitory potency of acetylcholinesterase. Additionally, docking studies suggest that studied compounds binds with the peripheral anionic site and not enter into the catalytic pocket due to the presence of the sterically extended substituent.

Meta-analysis of randomized controlled trials of galantamine in schizophrenia: significant cognitive enhancement

Cognitive impairments are core features of schizophrenia and the best predictor of functional outcome. Cholinergic system and alpha-7 nicotinic acetylcholine (α7nACh) receptors are strongly implicated in the pathophysiologic mechanisms associated with cognitive impairments in schizophrenia. Galantamine is not only a reversible, competitive inhibitor of acetylcholinesterase but also a type I positive allosteric modulator of α7nACh receptors. The objective of this meta-analysis was to examine the efficacy of galantamine for cognitive symptoms of schizophrenia. In the meta-analysis that included six randomized controlled trials (RCTs, N=226), cognitive impairments significantly improved with galantamine compared to placebo, with a small Hedges’ g effect size of 0.233. This finding is consistent with other RCTs in schizophrenia with medications with a similar mechanism of action. On the basis of the results from all the failed (although some efficacy has been shown) RCTs to date in schizophrenia, targeting only one pathophysiologic mechanism may be insufficient to detect a clinically meaningful signal. Nicotinergic medications, like any other add-on medications, are unlikely to be effective as stand-alone medications. Hence, these medications may have to be combined with other medications with complementary mechanisms such as glutamatergic/N-methyl-D-aspartate systems to detect a meaningful effect size for the three domains of psychopathology.

Galanthamine production in tissue culture and metabolomic study on Amaryllidaceae alkaloids in Narcissus pseudonarcissus cv. Carlton

The Amaryllidaceae alkaloids e.g. galanthamine (Gal), lycorine and narciclasine are noted for their pharmaceutical properties. Gal is a long acting, selective, and competitive acetylcholinesterase inhibitor approved for the treatment of early to mid-stage Alzheimer's diseases. The biosynthesis of alkaloids by plants using in vitro systems has been considered as a tool for drug discovery and production since total chemical synthesis is not economic. The biosynthetic pathways, especially for Gal, are starting to be understood, but still far from complete. This study is emphasised on the yield from whole plant and developing cell culture systems for optimized alkaloid production.In vitro cultures of Narcissus pseudonarcissus (cv. Carlton) initiated from twin-scale explants cultured on Murashige and Skoog (MS) agar medium fortified with different concentrations of growth regulators, were screened for their ability to produce alkaloids through GC–MS (gas chromatography-mass spectrophotometry). Callus obtained mainly from the MS medium containing high concentration of auxins i.e. 20 mg/l NAA (naphthalene acetic acid), while media with low auxin (4 mg/l NAA) and MS basal medium gave bulblets with both white and green shoots. Regenerated bulblets developed from callus found in both high and low auxin MS media. Tissue culture derived materials (callus and bulblets) and field grown samples (bulb, basal plate and leaves) from 'Carlton' were analyzed for galanthamine content. The highest amount of galanthamine was obtained from basal plate tissue followed by bulb tissues, leaves, bulblets with green shoots, bulblets with white shoots and regenerated bulblets. Trace amount of galanthamine was found in callus.An NMR (nuclear magnetic resonance) based metabolomic analysis showed that the relative concentrations of compounds involved in phenylalanine and tyrosine metabolism, the initial stage biosynthetic pathways that yield the Amaryllidaceae alkaloids, were higher in field samples than in vitro samples which support the GC–MS findings of high Gal production in field samples.

New phosphazine and phosphazide derivatives as multifunctional ligands targeting acetylcholinesterase and β-Amyloid aggregation for treatment of Alzheimer's disease.

Phosphazine and phosphazide derivatives are described herein as a new class of selective and potent acetylcholinesterase (AChE) inhibitors and β-amyloid aggregation inhibitors. Phosphazines (5-7) were synthesized smoothly via a redox-condensation reaction of 1,2-bis(diphenylphosphino)ethane with different amines derivatives in the presence of dialkyl azodicarboxylate (Staudinger reaction) while phosphazides (8) via electrophilic attack of azido derivatives. Structures of the synthesized compounds were justified on the basis of compatible elementary and spectroscopic analyses. All the compounds were evaluated for their acetylcholinesterase inhibitory activity. The most three potent compounds (5b-c and 8b) showing AChE IC50 values (29.85-34.96nM) comparable to that of donepezil (34.42nM) were subjected to further investigation by testing their butyrylcholinesterase, MMP-2 and self-induced Aβ aggregation inhibition activity. Especially, the coumarin phosphazide derivative (8b) presented the best AChE inhibition selectivity index (IC50=34.96nM, AChE/BuChE; 3.81) together with good inhibition ability against MMP-2 (IC50=441.33nM) and self-induced Aβ1-42 aggregation (IC50=337.77nM). In addition, the inhibition of metal-induced Aβ aggregation by 8b was confirmed by thioflavine T fluorescence. The most potent effect of 8b was observed on the Zn2+-induced Aβ42 aggregation. Kinetic study of compound 8b suggested it to be a competitive AChE inhibitor. Also, it specifically chelates metal and is predicted to be permeable to BBB. It also possesses low toxicity on SH-SY5Y neuroblastoma cells with a safety index of 15.37. In addition, it was demonstrated that compound 8b can improve the cognitive impairment of scopolamine-induced model in mice with % alternations and transfer latency time comparable to that of donepezil. Also, a docking study was carried out and it was in accordance with the in vitro results. These promising in vitro and in vivo findings highlight compound 8b as a possible drug candidate in searching for new multifunctional AD drugs.

Galantamine improves functional recovery and reduces lesion size in a rat model of spinal cord injury

Spinal cord injury (SCI) is a medical condition that currently lacks effective treatment. Galantamine is a reversible, competitive acetylcholinesterase inhibitor, used to treat patients with Alzheimeŕs disease. It has been demonstrated that galantamine increases cerebral neurogenesis and has a neuroprotective effect by binding to nicotinic receptors and has an anti-inflammatory effect due to its allosteric binding to the α7nAChR. In the present study, the effects of galantamine on functional recovery and histological outcome in a rat contusion model of SCI were analyzed. Male Wistar rats were submitted to SCI using a NYU/MASCIS impactor. The animals from the galantamine group were treated with 5 mg/kg galantamine intraperitoneally for 5 days. The Basso, Beattie and Bresnahan scale (BBB) was used to evaluate locomotor activity. The expression of beta3-tubulin, NFM, GFAP, O4, CD68 and CD3 was analyzed by flow cytometry. Rats that received galantamine had significantly higher BBB scores in comparison with the control lesion group. Galantamine treatment increased the percentage of NFM positive cells at 6 weeks post-injury and reduced the size of the lesion. The results indicate that galantamine increased tissue survival and accelerated hind limb motor function recovery. This is the first study that has shown the possibility of therapeutic use of galantamine in a model of acute spinal cord injury.

In vitro and in silico evaluation of fucosterol from Sargassum horridum as potential human acetylcholinesterase inhibitor

The fucosterol has been reported numerous biological activities. In this study, the activity in vitro of the fucosterol from Sargassum horridum as potential human acetylcholinesterase inhibitor was evaluated. The structural identification was obtained by nuclear magnetic resonance (NMR) spectroscopy and based on experimental data, we combined docking and molecular dynamics simulations coupled to the molecular-mechanics-generalized-born-surface-area approach to evaluating the structural and energetic basis for the molecular recognition of fucosterol and neostigmine at the binding site of acetylcholinesterase (AChE). In addition, the Lineweaver–Burk plot showed the nature of a non-competitive inhibition. The maximum velocity (Vmax) and the constant of Michaelis–Menten (Km) estimated for fucosterol (0.006 µM) were 0.015 1/Vo (ΔA/h and 6.399 1/[ACh] mM−1, respectively. While, for neostigmine (0.14 µM), the Vmax was 0.022 1/Vo (ΔA/h) and Km of 6.726 1/[ACh] mM−1, these results showed a more effective inhibition by fucosterol respect to neostigmine. Structural analysis revealed that neostigmine reaches the AChE binding site reported elsewhere, whereas fucosterol can act as a no-competitive and competitive acetylcholinesterase inhibitor, in agree with kinetic enzymatic experiments. Binding free energy calculations revealed that fucosterol reaches the acetylcholinesterase binding site with higher affinity than neostigmine, which is according to experimental results. Whereas the per-residue decomposition free energy analysis let us identify crucial residues involved in the molecular recognition of ligands by AChE. Results corroborate the ability of theoretical methods to provide crucial information at the atomic level about energetic and structural differences in the binding interaction and affinity from fucosterol with AChE.Communicated by Ramaswamy H. Sarma

The insight of in vitro and in silico studies on cholinesterase inhibitors from the roots of Cimicifuga dahurica (Turcz.) Maxim.

Cholinesterases (ChEs) are enzymes that break down neurotransmitters associated with cognitive function and memory. We isolated cinnamic acids (1 and 2), indolinones (3 and 4), and cycloartane triterpenoid derivatives (5–19) from the roots of Cimicifuga dahurica (Turcz.) Maxim. by chromatography. These compounds were evaluated for their inhibitory activity toward ChEs. Compound 1 was determined to have an IC50 value of 16.7 ± 1.9 μM, and to act as a competitive inhibitor of acetylcholinesterase (AChE). Compounds 3, 4 and 14 were found to be noncompetitive with IC50 values of 13.8 ± 1.5 and 6.5 ± 2.5 μM, and competitive with an IC50 value of 22.6 ± 0.4 μM, respectively, against butyrylcholinesterase (BuChE). Our molecular simulation suggested each key amino acid, Tyr337 of AChE and Asn228 of BuChE, which were corresponded with potential inhibitors 1, and 3 and 4, respectively. Compounds 1 and 4 were revealed to be promising compounds for inhibition of AChEs and BuChEs, respectively.

Acquired Localized Hypertrichosis Induced by Rivastigmine.

Hypertrichosis is the excessive hair growth in any area of the skin surface. Acquired localized hypertrichosis may be secondary to multiple causes and there is a secondary form due to several drugs, which is usually reversible with discontinuation of the causative agent. Rivastigmine is a reversible and competitive inhibitor of acetylcholinesterase and butyrylcholinesterase used for symptomatic treatment of Alzheimer dementia and Parkinson's disease. It has an adequate safety profile and cutaneous side effects are unusual. Irritant contact dermatitis, allergic dermatitis, baboon syndrome, and cutaneous rash due to rivastigmine have been reported. We report on a Caucasian 80-year-old male with personal history of Alzheimer's disease. The patient started therapy with oral rivastigmine one month prior to clinical presentation of localized hypertrichosis on both forearms. Norgalanthamine has been shown to promote hair growth activity via the proliferation of dermal papilla. Acetylcholinesterase inhibitors can induce hair growth.

Huperzine A Alleviates Mechanical Allodynia but Not Spontaneous Pain via Muscarinic Acetylcholine Receptors in Mice.

Chronic pain is a major health issue and most patients suffer from spontaneous pain. Previous studies suggest that Huperzine A (Hup A), an alkaloid isolated from the Chinese herb Huperzia serrata, is a potent analgesic with few side effects. However, whether it alleviates spontaneous pain is unclear. We evaluated the effects of Hup A on spontaneous pain in mice using the conditioned place preference (CPP) behavioral assay and found that application of Hup A attenuated the mechanical allodynia induced by peripheral nerve injury or inflammation. This effect was blocked by atropine. However, clonidine but not Hup A induced preference for the drug-paired chamber in CPP. The same effects occurred when Hup A was infused into the anterior cingulate cortex. Furthermore, ambenonium chloride, a competitive inhibitor of acetylcholinesterase, also increased the paw-withdrawal threshold but failed to induce place preference in CPP. Therefore, our data suggest that acetylcholinesterase in both the peripheral and central nervous systems is involved in the regulation of mechanical allodynia but not the spontaneous pain.

Galanthamine biosynthesis in plant in vitro systems

The Amaryllidaceae alkaloid galanthamine (Gal) is a long‐acting, selective, reversible, and competitive acetylcholinesterase inhibitor used for the treatment of early‐ to mid‐stage Alzheimer's disease, poliomyelitis, and other neurological diseases. Currently, Gal is produced by extraction from plants such as daffodils (Narcissus cultivar Carlthon), snowflake (Leucojum aestivum), “red‐tubed lily” (Lycoris radiata), and Ungernia victoria, and alternatively by chemical synthesis. Due to the increased demand by the generic pharmaceutical companies and the limited availability of plant sources, the biosynthesis of Gal by plant in vitro systems has been considered as an alternative approach for its sustainable production. The present article reviews the state of the art of in vitro Gal biosynthesis including growth regulators, medium components, culture conditions, elicitation, and bioreactor systems. It may be used as a starting point for further studies in this area leading to a progress in biotechnological production of this valuable alkaloid.

Galantamine attenuates some of the subjective effects of intravenous nicotine and improves performance on a Go No-Go task in abstinent cigarette smokers: a preliminary report.

Galantamine (GAL), a reversible and competitive inhibitor of acetylcholinesterase, is used clinically in the treatment of Alzheimer's dementia. Some preclinical and clinical studies support the potential efficacy of cholinesterase inhibitors for smoking cessation, although their effects on the behavioral and physiological responses to nicotine have not been examined. The goal of this study was to characterize GAL's actions on multiple outcomes, including withdrawal severity and cognitive performance, as well as subjective and physiological responses to nicotine administered intravenously. A total of 12 smokers participated in a double-blind, placebo-controlled, crossover study. Smokers had two 4-day treatment periods, assigned in random sequence, to GAL (8 mg/day) or placebo treatment. On day 4 of each treatment phase, smokers had an experimental session in which they received an intravenous (IV) dose of saline or 1 mg/70 kg nicotine, 1 h apart, in a random order. GAL attenuated the self-reported rating of "craving for cigarettes" and prevented decrements in performance in a Go/No-Go task. In response to IV nicotine, GAL treatment attenuated the self-report ratings of "like the drug effects," "good drug effects," "bad drug effects," and "stimulated." These findings support the potential utility of GAL as a treatment for smoking cessation.

Galantamine improves sustained attention in chronic cocaine users.

Chronic cocaine users are known to have cognitive deficits that are predictive of poor treatment response. Whether these deficits improve with medications targeting specific cognitive functions has not been examined in previous studies. The goal of this study was to evaluate galantamine's efficacy on selected cognitive outcomes, including measures of sustained attention, response inhibition, and attentional bias in recently abstinent cocaine users. Galantamine, a reversible and competitive inhibitor of acetylcholinesterase, is used clinically in the treatment of Alzheimer's dementia. In a randomized, double-blind, parallel-group study, 34 participants were randomized to galantamine (8 mg/day) or placebo treatment for 10 days. Cognitive and self-report mood measures were obtained at baseline and on Days 5 and 10 after the initiation of treatment. Galantamine treatment, compared to placebo, improved the reaction time, F(2, 50) = 8.6, p < .01, detection sensitivity (A'), F(2, 50) = 4.9, p < .03, number of hits, F(2, 50) = 4.2, p < .04, and number of correct rejections, F(2, 50) = 5.6, p < .02, on the Rapid Visual Information Processing task. With the exception of speeding the reaction time on the Stroop, galantamine did not affect performance on other tasks, (p > .05). These results demonstrate that medications can enhance cognitive function (e.g., sustained attention) in abstinent cocaine users. The potential efficacy of galantamine as a treatment for cocaine abuse needs to be further evaluated in clinical trials.

Highly Efficient Detector of the Neurotransmitter ACh and AChE Inhibitors

AbstractAmong the variety of applications for biosensorsone of the exciting frontiers is to utilize those devices as post-synaptic sensing elements in chemical coupling between neurons and solid-state systems. The first necessary step to attain this challenge is to realize highly efficient detector for neurotransmitter acetylcholine (ACh). Herein, we demonstrate that the combination of floating gate configuration of ion-sensitive field effect transistor (ISFET) together with diluted covalent anchoring of enzyme acetylcholinesterase (AChE) onto device sensing area reveals a remarkable improvement of a four orders of magnitude in dose response to ACh. This high range sensitivity in addition to the benefits of peculiar microelectronic design show, that the presented hybrid provides a competent platform for assembly of artificial chemical synapse junction. Furthermore, our system exhibits clear response to eserine, a competitive inhibitor of AChE, and therefore it can be implemented as an effective sensor of pharmacological reagents, organophosphates, and nerve gases as well.

Chemical Synthesis of Galantamine, an Acetylcholinesterase Inhibitor for Treatment of Alzheimer′s Disease

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Study of a potential inhibitor of acetylcholinesterase using UV spectrophotometry, NMR spectroscopy and molecular modeling

Abstract1‐[6‐(Acridine‐9‐carbonyloxy)hexyl]pyridinium chloride (1) was synthesized and studied as a potential inhibitor of acetylcholinesterase (AChE), which is frequently involved in Alzheimer's disease. UV spectrophotometry showed that 1 is a reversible and competitive inhibitor of AChE (Ki ≈ 2 × 10−7 M). NMR (TrNOESY) showed that 1, bonded to AChE, maintains an extended form that allows hydrophobic interactions to occur between the aliphatic chain and the deep and narrow gorge of AchE and favors interactions between the acridine group and the catalytic and anionic subsites situated at the bottom of the gorge, and also between the pyridinium ring and the peripheral site. A more detailed picture of the structure of the complex was obtained by combining NMR structural data and molecular modeling (docking, dynamics simulation and energy calculations). Copyright © 2006 John Wiley &amp; Sons, Ltd.

Galanthamine, a Natural Product for the Treatment of Alzheimers Disease

(-)-Galanthamine is a selective, reversible competitive acetylcholinesterase inhibitor that has been recently approved for the symptomatic treatment of Alzheimer's disease. Galanthamine is a natural product belonging to the Amaryllidaceae family of alkaloids. The pharmacological history of galanthamine shows that the bioactive compound was discovered accidentally in the early 1950s, and the plant extracts were initially used to treat nerve pain and poliomyelitis. In addition, galanthamine had since been tested for use in anesthesiology, from facial nerve paralysis to schizophrenia. Galanthamine is a long-acting, selective, reversible and competitive AChE inhibitor that has recently been tested in AD patients and found to be readily absorbed, to be a performance enhancer on memory tests in some patients, and to be well tolerated, although some cholinergic side effects were observed. A number of total synthetic approaches have been reported, and a method for the industrial scale-up preparation of galanthamine is now being developed and patented. A variety of galanthamine derivatives have also been synthesized aiming to develop an agent free from cholinergic adverse effects. Galanthamine is a natural product that complements other synthetic drugs for the management of AD. In this account we will review the recent patent literature showing the most important advance on the chemistry of galanthamine.

Chemical synthesis of galantamine, an acetylcholinesterase inhibitor for treatment of Alzheimer’s disease

(-)-Galantamine, an alkaloid isolated from the Caucasian snow-drop (Galanthus woronowii), is a selective, reversible and competitive inhibitor of acetylcholinesterase (AChE), as well as an allosteric modulator of the neural nicotinic receptor for acetylcholine. Galantamine is the most recently approved AChE inhibitor for the symptomatic treatment of Alzheimer’s disease. Because of the limited supplies from natural sources, several total syntheses have been reported to produce this drug. Galantamine has attracted both the interest of organic chemists and pharmacologists in a collaborative effort directed to design, prepare and evaluate more biologically active molecules for the treatment of Alzheimer’s disease. In this review the recent patent literature will be reviewed, showing the most important chemical and/or biochemical advances of the chemistry and biology of galantamine.