Development of an in-vivo active reversible butyrylcholinesterase inhibitor (original) (raw)
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Acetyl cholinesterase: a potential target for Alzheimer’s disease intervention
Journal of Patan Academy of Health Sciences, 2020
Alzheimer's disease is a neurological disorder in which the death of brain cells causes memory loss and cognitive decline. The role of treatment is not limited to pharmacology, but also involves many factors, such as the psychological, social, and economic aspects of the patient and family. It is important to consider the use of AChe inhibitors in patients with mild to moderate AD, despite cost issues and in the absence of any other immediate progression. Although there are allots of currently available inhibitor for acetyl cholinesterase but there is no selective potent inhibitor for AD. so, there is an urgent need discover of compounds that are active against Acetyl cholinesterase, along with there is need of molecular modeling for identifying functional groups that may be important for inhibiting Acetyl cholinesterase activity.
Butyrylcholinesterase: An Important New Target in Alzheimers Disease Therapy
International Psychogeriatrics, 2002
Acetylcholinesterase (AChE) predominates in the healthy brain, with butyrylcholinesterase (BuChE) considered to play a minor role in regulating brain acetylcholine (ACh) levels. However, BuChE activity progressively increases in patients with Alzheimer's disease (AD), while AChE activity remains unchanged or declines. Both enzymes therefore represent legitimate therapeutic targets for ameliorating the cholinergic deficit considered to be responsible for the declines in cognitive, behavioral and global functioning characteristic of AD. The two enzymes differ in substrate specificity, kinetics and activity in different brain regions. Experimental evidence from the use of agents with enhanced selectivity for BuChE (cymserine analogues, MF-8622) and the dual inhibitor of both AChE and BuChE, rivastigmine, indicates potential therapeutic benefits of inhibiting both AChE and BuChE in AD and related dementias. Recent evidence suggests that both AChE and BuChE may have roles in the aetiology and progression of AD beyond regulation of synaptic ACh levels. The development of specific BuChE inhibitors and further experience with the dual enzyme inhibitor rivastigmine will improve understanding of the aetiology of AD and should lend to a wider variety of potent treatment options.
2010
All approved drugs for Alzheimer disease (AD) in clinical practice ameliorate the symptoms of the disease. Among them, acetylcholinesterase inhibitors (AChEIs) are used to increase the cholinergic activity. Among new AChEI, tacrine compounds were found to be more toxic compared to 7-MEOTA (9amino-7-methoxy-1,2,3,4-tetrahydroacridine). In this Letter, series of 7-MEOTA analogues (N-alkyl-7methoxytacrine) were synthesized. Their inhibitory ability was evaluated on recombinant human acetylcholinesterase (AChE) and plasmatic human butyrylcholinesterase (BChE). Three novel compounds showed promising results towards hAChE better to THA or 7-MEOTA. Three compounds resulted as potent inhibitors of hBChE. The SAR findings highlighted the C 6 -C 7 N-alkyl chains for cholinesterase inhibition.
Research Article New Acetylcholinesterase Inhibitors for Alzheimer’s Disease
Acetylcholinesterase (AChE) remains a highly viable target for the symptomatic improvement in Alzheimer's disease (AD) because cholinergic deficit is a consistent and early finding in AD. The treatment approach of inhibiting peripheral AchE for myasthenia gravis had effectively proven that AchE inhibition was a reachable therapeutic target. Subsequently tacrine, donepezil, rivastigmine, and galantamine were developed and approved for the symptomatic treatment of AD. Since then, multiple cholinesterase inhibitors (ChEI) continue to be developed. These include newer ChEIs, naturally derived ChEIs, hybrids, and synthetic analogues. In this paper, we summarize the different types of ChEIs in development and their respective mechanisms of actions. This pharmacological approach continues to be active with many promising compounds.
Bioinformation, 2018
Acetyl-cholinesterase enzyme (AChE) is a known target for identifying potential inhibitors against Alzheimer diseases (AD). Therefore, it is of interest to screen AChE with the CNS-BBB database. An AChE enzyme is a member of hydrolase family is activated by acetylcholine (ACh), so, targeting the AChE enzyme with the potential inhibitor may block the binding of the ACh. In this study we carried out virtual screening of drug-like molecules from Chemical Diversity Database particularly CNS-BBB compounds, to identify potential inhibitors using Glide docking program. Top ranking ten compounds, which have lower Glide Score when compared to known drugs (Tacrine and Galantamine) for AChE. For top three molecules MD simulation was carried out and calculated binding free energy. We report the best binding compounds with AChE compared to known drugs (Taine and Galantamine) for AD. We further document the salient features of their molecular interaction with the known target. Three molecules (1-benzyl-3-(2hydroxyethyl)-N-[2-(3-pyridyl)ethyl]-3-pyrrolidinecarboxamide, N-{3[benzyl(methyl)amino]propyl}-1,5-dimethyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]quinoline-2-carboxamide, and 6-chloro-N-[2-(diethylamino)-2-phenylethyl]-4-oxo-4H-chromene-2-carboxamide) have-196.36,-204.27,-214.40 kJ/mol, binding free energy values respectively which are much lower than values calculated for the reference ligands Tacrine and Galantamine having-119.65 and-142.18 kJ/mol respectively. Thus these molecules can be very novel potential inhibitors against AChE involved in Alzheimer's disease.
Novel Hybrid Molecules of Cholinesterase Inhibitor for Alzheimer’s Disease: A Systematic Review
2017
Acetylcholinesterase (AChE) inhibitor is a basic drug design recently used in treating Alzheimer’s disease (AD). However, butyrylcholinesterase (BuChE) also suggested to be responsible for the hydrolysis of acetylcholine (ACh) and its inhibition may benefit in the latter stage of AD. Nonetheless, the search for potent AChE and BuChE inhibitor is still in need, in curing this neurodegenerative disorders. Numerous hybrid molecules were designed for the dual inhibition of AChE and BuChE. However, these molecules have different selectivity towards AChE and BuChE. Therefore, this systematic review aims to determine a rational design that can exhibit high inhibition against AChE and BuChE activity. ScienceDirect, Pubmed, Medline & Ovid and ISI Web of Science database from January 2006 to September 2016 were searched systematically with some specific inclusive and exclusive criterias. The synthesis of hybrid molecules and anticholinesterase (AChE and BuChE) test conducted in human AChE and...
New Acetylcholinesterase Inhibitors for Alzheimer&# 39; s Disease
International Journal of Alzheimer's …, 2011
Acetylcholinesterase (AChE) remains a highly viable target for the symptomatic improvement in Alzheimer's disease (AD) because cholinergic deficit is a consistent and early finding in AD. The treatment approach of inhibiting peripheral AchE for myasthenia gravis had effectively proven that AchE inhibition was a reachable therapeutic target. Subsequently tacrine, donepezil, rivastigmine, and galantamine were developed and approved for the symptomatic treatment of AD. Since then, multiple cholinesterase inhibitors (ChEI) continue to be developed. These include newer ChEIs, naturally derived ChEIs, hybrids, and synthetic analogues. In this paper, we summarize the different types of ChEIs in development and their respective mechanisms of actions. This pharmacological approach continues to be active with many promising compounds.