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Synthesis and acetylcholinesterase/butyrylcholinesterase inhibition activity of arecoline-, 4-thiazolidinone- and piperidine- based conjugates
Abstract
Objective: The aim of the study is to design, synthesize and identification of novel acetylcholinesterase/butyrylcholinesterase (AChE/BuChE) inhibitors. Methods: The AChE and BuChE inhibition activity of a library of piperidine and 4-thiazolidinone substituted arecoline derivatives are described. The chemical structures of newly synthesized compounds were confirmed by IR,1H NMR,13C NMR and mass spectral analysis. Results: The cholinesterase inhibition assays indicated that few of the synthesized compounds exhibited considerable activity at micromolar range for AChE over BuChE. Compound 7c exhibited the most potent AChE inhibitory activity with an IC50value of 6.62 μM for AChE and 13.78 μM for BuChE, which is comparable to the standard Neostigmine with an IC502.05 μM for AChE and 3.64 μM for BuChE respectively. Conclusion: Our results clearly demonstrate that arecoline-4-thiazolidinone derivatives open up a new avenue in the field of Alzheimer’s disease. © 2015, Asian Journal of Pharmaceutical and Clinical Research. All rights reserved.
... Recognizing the significance of hybrid scaffolds comprising two or more biologically active moieties, we have synthesized hybrid scaffolds that feature benzoxazole combined with thiazolidinone derivatives. Our goal is to enhance their anti-Alzheimer's activity in the search for potential lead compounds [34][35][36][37][38] (Fig. 4). ...
Benzoxazole-based thiazolidinone hybrids derivatives (1–19) were afforded and further subjected to in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition studies for the first time. All these analogues were found to display good inhibition against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE)enzymes with IC50 values 4.20 ± 1.10 μM to 43.20 ± 4.50 μM (against AChE) and 3.80 ± 1.20 μM to 34.50 ± 3.30 μM (against BuChE) as compared to standard donepezil having IC50 values of 21.86 ± 0.40 μM (against AChE) and 32.47 ± 2.30 μM (against BuChE) respectively. Specifically, compound 16, characterized by a 3,4-dichloro substitution on ring B and 2–OH and 4-CF3 substitutions on ring C, along with compound 13, having 2,4-diCl on ring B and 2-OH and 4-CF3 on ring C, were identified as the most potent inhibitors of the targeted AChE and BuChE enzymes, even manifolds more potent than standard donepezil drug. The structures of all synthesized analogues were verified through the utilization of multiple spectroscopic techniques, including HREI-MS and NMR (1H NMR and 13C NMR). The structure-activity relationship (SAR) demonstrated that analogs bearing electron withdrawing groups such as –CF3, –Cl and -NO2 groups displayed superior AChE and BuChE activities. In the molecular docking analysis of the most potent analogs, a favorable protein-ligand interaction (PLI) profile was observed with the respective targets (AChE and BuChE). These interactions encompassed crucial bonding types such as hydrogen bonding, π-π interactions, π-π stacking, and hydrophobic interactions.
... Recognizing the significance of hybrid scaffolds comprising two or more biologically active moieties, we have synthesized hybrid scaffolds that feature benzoxazole combined with thiazolidinone derivatives. Our goal is to enhance their anti-Alzheimer's activity in the search for potential lead compounds [34][35][36][37][38] (Fig. 4). ...
... Plant-derived and synthetic piperidines are extremely important for their antioxidant properties [41][42][43]. For example, naturally occurred piperidine alkaloids demonstrated promising bactericidal, anticancer, and antioxidant properties [44]. ...
Piperidine is a saturated heterocyclic ring, considered as a privileged scaffold in view of its role in wide range of biological activities. Piperidine is good candidate molecule for obtaining potent antioxidant agents. The planar nature of this heterocyclic nucleus allows the introduction of substituent groups at different positions on the ring. In the present review, the antioxidant profile of piperidine containing compounds has been focused. The compounds were classified into naturally occurring piperidines, unsaturated piperidines, N-substituted piperidines, piperamides, piperanols, piperidine oximes, and hydrazides.
A series of twenty bis ‐thiazolidinone based chalcone scaffolds (1‐20) were synthesized and characterized by using various spectroscopic tools such as HR‐EI‐MS, 1 HNMR, 13 CNMR and were screened in vitro for their AChE and BuChE inhibition profile. It was noteworthy, that all the synthetic analogues (except analogues 10, 12 and 1 4 , which are found to be inactive) showed moderate to good inhibitory potentials on screening against AchE and BuChE enzymes with IC 50 values ranging from 0.10 ±0.050 to 7.60 ± 0.10 µM and 0.10 ± 0.050µM to 10.70 ± 0.20 µM as compared to standard Donepezil inhibitor (IC 50 = 0.016 ± 0.12 µM), (IC 50 = 4.5 ± 0.11 µM). Among the current series, analogue 20 (IC 50 = 0.10 ± 0.050µM), (IC 50 = 0.10 ± 0.050µM) bearing trihydroxy substitutions on ortho ‐, meta ‐ and para ‐position of both rings A and B , respectively was found to be the most active inhibitor of AChE and BuChE enzymes . Analogue 19 (IC 50 = 0.20 ± 0.050 µM), (IC 50 = 0.20 ± 0.050µM) bearing dihydroxy substitutions on ortho ‐ and meta ‐position of both ring A and ring B respectively, was identified as the second most potent inhibitor against both these enzymes. Potent analogs were further subjected to molecular docking study to identify the binding interactions with enzymes active site. SAR study was done for all the analogues mostly based on substitution pattern on both ring A and B respectively.
Twenty novel 7-benzyloxycoumarin based compounds were synthesized with a variety of bioactive chemical fragments. The synthesized compounds showed remarkable acetylcholinesterase (AChE) inhibitory activity. In vitro assay revealed that compounds 7-benzyloxy-4-{[(4-phenylthiazol-2(3H)-ylidene)hydrazono]methyl}-2H-chromen-2-one (5b , IC50= 0.451 μM), 7-benzyloxy-4-({[4-(4-methoxyphenyl)thiazol-2(3H)-ylidene]hydrazono}methyl)-2H-chromen-2-one (5d, IC50= 0.625 μM), 5-amino-1-[2-(7-benzyloxy-2-oxo-2H-chromen-4-yl)acetyl]-1H-pyrazole-4-carbonitrile (13c, IC50= 0.466 μM), 2-(7-benzyloxy-2-oxo-2H-chromen-4-yl)-N-(2-methylimino-4-phenylthiazol-3(2H)-yl)acetamide (16a, IC50= 0.500 μM) and 2-(7-benzyloxy-2-oxo-2H-chromen-4-yl)-N-[4-(4-methoxyphenyl)-2-methyliminothiazol-3(2H)-yl]acetamide (16b, IC50= 0.590 μM) exhibited promising AChE inhibitory activity even better than donepezil (IC50= 0.711 μM). Kinetic study for compound 5b implied mixed type inhibitor which could bind peripheral anionic site (PAS) and catalytic active site (CAS) of AChE enzyme. In addition, in vivo evaluation of compounds 5b, 13c and 16a confirmed significant memory improvement in scopolamine-induced impairment model in tested mice. Furthermore, in silico studies were performed on the synthesized compounds which included molecular docking study at the active site of recombinant human acetylcholinesterase enzyme (rhAChE) as well as prediction of ADMET and other physicochemical parameters. A correlation between the docking results and IC50 of tested compounds was routinely observed and shared similar binding pattern to the co-crystallized ligand donepezil.
Twenty four 6-aminocoumarin based derivatives were synthesized according to two schemes. All the compounds were screened for their acetylcholinesterase inhibitory activity where compound 5b proved to be the most potent AChE inhibitor with (IC50 = 37 nM) compared to tacrine and donepezil (IC50 = 55.0 and 59.0 nM, respectively). Six compounds 2f, 2g, 4b, 5b, 8b and 9b revealed superior activity over donepezil and a conclusive structure activity relationship study was conducted explaining the obtained results. Furthermore, compounds 2f, 4b and 5b were investigated for their neurobehavioral effect in vivo. All the tested compounds showed improvement of neurobehavioral experiments using donepezil as reference drug. In addition, compounds 2f, 4b and 5b were able to reduce extracellular deposition of amyloid beta 42 in a comparable manner to donepezil. The binding modes of the synthesized compounds were evaluated in silico via molecular docking in the active site of AChE, as well as molecular dynamics simulation study. A pharmacophore model was generated for the newly synthesized compounds.
Acetylcholinesterase is involved in the termination of impulse transmission by rapid hydrolysis of the neurotransmitter acetylcholine in numerous cholinergic pathways in the central and peripheral nervous systems. The enzyme inactivation, induced by various inhibitors, leads to acetylcholine accumulation, hyperstimulation of nicotinic and muscarinic receptors, and disrupted neurotransmission. Hence, acetylcholinesterase inhibitors, interacting with the enzyme as their primary target, are applied as relevant drugs and toxins. This review presents an overview of toxicology and pharmacology of reversible and irreversible acetylcholinesterase inactivating compounds. In the case of reversible inhibitors being commonly applied in neurodegenerative disorders treatment, special attention is paid to currently approved drugs (donepezil, rivastigmine and galantamine) in the pharmacotherapy of Alzheimer's disease, and toxic carbamates used as pesticides. Subsequently, mechanism of irreversible acetylcholinesterase inhibition induced by organophosphorus compounds (insecticides and nerve agents), and their specific and nonspecific toxic effects are described, as well as irreversible inhibitors having pharmacological implementation. In addition, the pharmacological treatment of intoxication caused by organophosphates is presented, with emphasis on oxime reactivators of the inhibited enzyme activity administering as causal drugs after the poisoning. Besides, organophosphorus and carbamate insecticides can be detoxified in mammals through enzymatic hydrolysis before they reach targets in the nervous system. Carboxylesterases most effectively decompose carbamates, whereas the most successful route of organophosphates detoxification is their degradation by corresponding phosphotriesterases.
As acetylcholinesterase (AChE) inhibitors are an important therapeutic strategy in Alzheimer’s disease, efforts are being made in search of new molecules with anti-AChE activity. The fact that naturally-occurring compounds from plants are considered to be a potential source of new inhibitors has led to the discovery of an important number of secondary metabolites and plant extracts with the ability of inhibiting the enzyme AChE, which, according to the cholinergic hypothesis, increases the levels of the neurotransmitter acetylcholine in the brain, thus improving cholinergic functions in patients with Alzheimer’s disease and alleviating the symptoms of this neurological disorder. This review summarizes a total of 128 studies which correspond to the most relevant research work published during 2006-2012
(1st semester) on plant-derived compounds, plant extracts and essential oils found to elicit AChE inhibition.
Memory is the ability of an individual to record the information and recall it whenever needed. Dementia is a mental disorder characterized by loss of intellectual ability (judgment or abstract thinking) which invariably involves impairment of memory. The most common cause of dementia is Alzheimers disease (AD), which is a progressive neurodegenerative disorder associated with loss of neurons in distinct brain areas and cord. Stressful conditions are often associated with loss of memory and cognitive functions which may lead to threats of schizophrenia and AD. Traditionally herbal drugs have been used to enhance cognitive functions and to alleviate other functions associate with the AD. A number of medicinal plants per se and medicines derived from these plants have shown memory enhancing properties by virtue of their medicinal constituents. One of the mechanisms suggested to dementia is decreased cholinergic activity in brain. Therefore cholinergic drugs (of plant origin) like: muscarinic agonists (e.g. arecoline, pilocarpine etc.), nicotinic agonists (e.g. nicotine) and cholinesterase inhibitors (e.g. huperzine) can be employed for improving memory. Some other classes of drugs used in dementia are: stimulants or nootropics (e.g. piracetam, amphetamine), putative cerebral vasodilators (e.g. ergot alkaloids, papavarine), calcium channel blocker (e.g. nimodipine). Since allopathic system of medicine provides radical cure so more concentration is provided on natural products to cure dementia, and some excellent results with certain plants justified their use as memory enhancer. Traditional System of medicine already mentioned some plants while recent screening is also going on different plants. Examples of some plants showing promising activity in neuropsychopharmacology are: Allium sativum etc. Rapid industrialization has resulted into various neurons disorder in human which has forced us to look back for cure at our old age system of medicine that is Ayurveda. Keywords : 212 INTRODUCTION Learning is defined as acquisition of information and skills. Subsequent retention of this information is called as memory. In Ayurveda there are three aspects of mental ability 1. Dhi (Process of acquisition/Learning) 2. Dhuti (Process of retention) 3. Smriti (Process of recall) Any disturbance in these aspects resulted in the loss of mental ability. Dementia and other cognitive disorders like Alzheimers disease (AD) pose a challenge to physicians. Dementia is a serious and common problem that affects more than 4 million Americans and costs society more than $50 billion annually. 10% of persons over age 70 years and 20 to 40% of individuals over age 85 years have clinically identifiable memory loss. Dementia is a syndrome with many causes. A simple definition of dementia is a deterioration in cognitive abilities that impairs the previously successful performance of activities of daily living. Memory is the most common and most important cognitive ability that is lost. Other mental faculties may also be affected such as attention, judgment, comprehension, orientation, learning, calculation, problem solving, mood, and behavior. Agitation or withdrawal, hallucinations, delusions, insomnia, and loss of inhibitions are also common. Individuals with mental retardation and psychosis may become demented if a decline in intellectual function occurs. Many common forms of dementia are progressive, but some dementing illnesses are static and unchanging. Dementia is a chronic condition, whereas delirium is and acute confusional state associated with a change in level of consciousness (ranging from lethargy to agitation). Memory is a complex function of the brain that has fascinated philosophers and scientists for centuries. Memory is currently viewed as a mental process that uses several storage buffers of differing capacity and duration.
Background:
Cognitive enhancers, including cholinesterase inhibitors and memantine, are used to treat dementia, but their effectiveness for mild cognitive impairment is unclear. We conducted a systematic review to examine the efficacy and safety of cognitive enhancers for mild cognitive impairment.
Methods:
Our eligibility criteria were studies of the effects of donepezil, rivastigmine, galantamine or memantine on mild cognitive impairment reporting cognition, function, behaviour, global status, and mortality or harms. We identified relevant material by searching electronic databases (e.g., MEDLINE, Embase), the references of included studies, trial registries and conference proceedings, and by contacting experts. Two reviewers independently screened the results of the literature search, abstracted data and appraised risk of bias using the Cochrane risk-of-bias tool.
Results:
We screened 15,554 titles and abstracts and 1384 full-text articles. Eight randomized clinical trials and 3 companion reports met our inclusion criteria. We found no significant effects of cognitive enhancers on cognition (Mini-Mental State Examination: 3 randomized clinical trials [RCTs], mean difference [MD] 0.14, 95% confidence interval [CI] -0.22 to 0.50; Alzheimer's Disease Assessment Scale - cognition subscale: 3 RCTs, standardized MD -0.07, 95% CI-0.16 to 0.01]) or function (Alzheimer's Disease Cooperative Study activities of daily living inventory: 2 RCTs, MD 0.30, 95% CI -0.26 to 0.86). Cognitive enhancers were associated with higher risks of nausea, diarrhea and vomiting than placebo.
Interpretation:
Cognitive enhancers did not improve cognition or function among patients with mild cognitive impairment and were associated with a greater risk of gastrointestinal harms. Our findings do not support the use of cognitive enhancers for mild cognitive impairment.
The synapse is a localized neurohumoral contact between a neuron and an effector cell and may be considered the quantum of fast intercellular communication. Analogously, the postsynaptic neurotransmitter receptor may be considered the quantum of fast chemical to electrical transduction. Our understanding of postsynaptic receptors began to develop about a hundred years ago with the demonstration that electrical stimulation of the vagus nerve released acetylcholine and slowed the heart beat. During the past 50 years, advances in understanding postsynaptic receptors increased at a rapid pace, owing largely to studies of the acetylcholine receptor (AChR) at the motor endplate. The endplate AChR belongs to a large superfamily of neurotransmitter receptors, called Cys-loop receptors, and has served as an exemplar receptor for probing fundamental structures and mechanisms that underlie fast synaptic transmission in the central and peripheral nervous systems. Recent studies provide an increasingly detailed picture of the structure of the AChR and the symphony of molecular motions that underpin its remarkably fast and efficient chemoelectrical transduction.
Earlier we have reported the effect of arecoline thiazolidinone and morpholino arecoline derivatives as muscarinic receptor 1 agonists in Alzheimer's presenile dementia models. To elucidate further our Structure-Activity Relationship (SAR) studies on the chemistry and muscarinic receptor 1 binding efficacy, a series of novel carboxamide derivatives of 2-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)morpholine molecule have been designed and synthesized as a new class of M1 receptor agonists with a low toxicity effect profile that enhances memory function in animal models of Alzheimer's presenile dementia and also modulates the APP secretion from rat brain cerebrocortical slices by activating M1 receptor in vitro. Results suggest that compound 9b having methyl group at the para position of the aryl group attached to the carboxamide of morpholino arecoline could emerge as a potent molecule having antidementia activity.
Alzheimer's disease is one of the most common causes of mental deterioration in elderly people, accounting for around 50%-60% of the overall cases of dementia among persons over 65 years of age. The past two decades have witnessed a considerable research effort directed towards discovering the cause of Alzheimer's disease with the ultimate hope of developing safe and effective pharmacological treatments. This article examines the existing scientific applicability of the original cholinergic hypothesis of Alzheimer's disease by describing the biochemical and histopathological changes of neurotransmitter markers that occur in the brains of patients with Alzheimer's disease both at postmortem and neurosurgical cerebral biopsy and the behavioural consequences of cholinomimetic drugs and cholinergic lesions. Such studies have resulted in the discovery of an association between a decline in learning and memory, and a deficit in excitatory amino acid (EAA) neurotransmission, together with important roles for the cholinergic system in attentional processing and as a modulator of EAA neurotransmission. Accordingly, although there is presently no "cure" for Alzheimer's disease, a large number of potential therapeutic interventions have emerged that are designed to correct loss of presynaptic cholinergic function. A few of these compounds have confirmed efficacy in delaying the deterioration of symptoms of Alzheimer's disease, a valuable treatment target considering the progressive nature of the disease. Indeed, three compounds have received European approval for the treatment of the cognitive symptoms of Alzheimer's disease, first tacrine and more recently, donepezil and rivastigmine, all of which are cholinesterase inhibitors.
Alzheimer's disease is the most common cause of dementia in older people, with about half a million people affected in the UK. Its effects are devastating and far-reaching for sufferers, their carers and society in general – the Audit Commission estimated the annual cost of dementia care for 1998–1999 at £6.1 billion (Audit Commission, 2000). There is no cure and it is terminal within 3 to 7 years of diagnosis. Given an estimated doubling of dementia cases over the next 50 years (Melzer et al , 1997), the burden of care is set to increase substantially.
Propylphosphonic anhydride (T3P®)-DMSO mediated oxidation of alcohols to carbonyl compounds and their subsequent cyclization with aryl/hetero aryl amines and thioglycolic acid to afford 4-thiazolidinones has been reported. Synthesis of 4-thiazolidinones directly from alcohols has been carried out for the first time. Mild reaction conditions, wide functional group tolerance, ease of work-up, and good yields are the noteworthy features of this protocol.
Areca nut (Areca catechu) is chewed as a medical and psychoactive food by roughly 10% of the world population. Areca nut chewing may lead to low birth weight, premature delivery and impaired muscle development. Our previous study showed that arecoline, a major alkaloid in the areca nut, inhibited the myogenic differentiation of C2C12 myoblastic cells. The clustering of acetylcholine receptors (AChR) in the postsynaptic membrane at the neuromuscular junction (NMJ) by agrin, a signaling protein released by motor neurons, is critical for the development of functional muscles. Here, we further investigate whether arecoline affects the AChR clustering using cultured C2C12 myotubes. Rhodamine-conjugated α-bungarotoxin was used to detect the presence of AChR clusters. Our results showed that arecoline inhibited the formation of agrin-induced AChR clusters and destabilized agrin-induced or spontaneous AChR cluster formation. In addition, arecoline inhibited the expression of myogenin in C2C12 myotubes. These results shed light on the important role of arecoline on the detrimental effect of areca nut to muscle development.
A photometric method for determining acetylcholinesterase activity of tissue extracts, homogenates, cell suspensions, etc., has been described. The enzyme activity is measured by following the increase of yellow color produced from thiocholine when it reacts with dithiobisnitrobenzoate ion. It is based on coupling of these reactions: The latter reaction is rapid and the assay is sensitive (i.e. a 10 μ1 sample of blood is adequate). The use of a recorder has been most helpful, but is not essential. The method has been used to study the enzyme in human erythrocytes and homogenates of rat brain, kidney, lungs, liver and muscle tissue. Kinetic constants determined by this system for erythrocyte eholinesterase are presented. The data obtained with acetylthiocholine as substrate are similar to those with acetylcholine.
Earlier we have reported the effect of arecoline thiazolidinone and morpholino arecoline analogues as muscarinic receptor 1 agonist in Alzheimer's dementia models. To elucidate further our SAR study on the chemistry and muscarinic receptor binding efficacy, a series of novel N-alkyl/aryl substituted thiazolidinone arecoline analogues 6(a-m) were designed and synthesized from 3-pyridine carboxaldehyde by reacting with different amines in the presence of gamma-ferrite as catalyst and subjected to in vitro muscarinic receptor binding studies using male Wistar rat brain membrane homogenate and extended to in vivo pharmacological evaluation of memory and learning in male Wistar rats. Derivative 6j having diphenylamine moiety attached to nitrogen of thiazolidinone showed significant affinity for the M1 receptor binding.
Neuropsychological tests can assist the neurologist in answering the following questions: Does a given patient have any acquired impairment of intellectual functioning? If so, does this impairment appear to be typical of Alzheimer's-type dementia or do the test results suggest some other contributor of this decline? Have the patient's higher cortical functions deteriorated, improved, or stabilized since the last evaluation? Does a given patient have pseudodementia or dementia? Is a given demented patient capable of living independently or is the patient in need of care in some institutional setting?
The cholinergic hypothesis claims that the decline in cognitive functions in dementia is predominantly related to a decrease in cholinergic neurotransmission. This hypothesis has led to great interest in the putative involvement of the cholinergic neurotransmission in learning and memory processes. This review aims to assess the data of studies in which the role of acetylcholine (ACh) in cognitive functions was investigated. For this purpose, studies from three different fields of research, namely: (1) behavioral pharmacology (effects of drugs on behavior); (2) behavioral neuroscience (effects of brain lesions on behavior); and (3) dementia, are discussed separately. The experimental tools that have been used in pharmacological studies may appear to be inadequate to enable conclusions to be drawn about the involvement of ACh in learning and memory processes. Especially, the use of scopolamine as a pharmacological tool is criticized. In the field of behavioral neuroscience a highly specific cholinergic toxin has been developed. It appears that the greater and more specific the cholinergic damage, the fewer effects can be observed at the behavioral level. The correlation between the decrease in cholinergic markers and the cognitive decline in dementia may not be as clearcut as has been assumed. The involvement of other neurotransmitter systems in cognitive functions is briefly discussed. Taking into account the results of the different fields of research, the notion that ACh plays a pivotal role in learning and memory processes seems to be overstated. Even when the role of other neurotransmitter systems in learning and memory is taken into consideration, it is unlikely that ACh has a specific role in these processes. On basis of the available data, ACh seems to be more specifically involved in attentional processes than in learning and memory processes.
To study the pharmacokinetics and pharmacodynamics of intravenously administered arecoline in subjects with Alzheimer's disease.
Plasma arecoline concentrations were measured during and after high-dose (i.e., 5 mg intravenously over 30 minutes) and up to 2 weeks of continuous multiple-dose steady-state intravenous infusions of arecoline in 15 subjects with mild to moderate Alzheimer's disease. During multiple-dose infusions, the dose of arecoline was escalated from 0.5 to 40 mg/day. Psychometric tests were administered at baseline and every other dose to determine an "optimal dose" for each subject. This dose then was administered for 1 week using a randomized, placebo-controlled, double blind, crossover design. Plasma drug concentrations were measured by GC-MS.
The optimal dose of arecoline varied fourfold across subjects (4 mg/day, n = 6; 16 mg/day, n = 3) with mean plasma half-lives of 0.95 +/- 0.54 and 9.3 +/- 4.5 (SD) minutes. Clearance and volume of distribution were 13.6 +/- 5.8 L/min and 205 +/- 170 (SD) L, respectively. At the dose that optimized memory, the mean plasma level was 0.31 +/- 0.14 (SD) ng/ml, and it predicted the optimal dose in all subjects.
Because optimal dose variation is due to differing plasma kinetics, the plasma arecoline level measured at a single infusion rate can be used to choose the optimal dose for memory enhancement in patients with Alzheimer's disease.
Male Sprague-Dawley rats, preoperatively trained in a 1-h delay non-match-to-position radial maze task, received bilateral stereotaxic injections of a selective cholinotoxin, ethylcholine aziridinium ion (AF64A: 3 nmol/3 microliters/lateral ventricle). Animals treated with AF64A made significantly more total postdelay errors than vehicle controls. Sustained delivery, via miniosmotic pumps, of arecoline (0.1, 0.3, 1, 3, 10, or 30 mg/kg/day sc for 14 days) attenuated the AF64A-induced cognitive impairment in a dose-dependent manner, producing an inverted U-shaped dose-response function which was optimal at 1.0 mg/kg/day. Following these studies, choline acetyltransferase activity was significantly reduced in hippocampi extracted from the AF64A-treated rats, indicating successful cholinotoxicity. This paradigm may be useful as a possible screen for potential Alzheimer's disease therapeutic agents. This conclusion is supported by published reports of beneficial arecoline effects observed following 2-week intravenous infusions in patients with Alzheimer's disease (Soncrant, Raffaele, Asthana, Berardi, Morris, & Haxby, 1993).
Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the elderly, characterised by widespread loss of central cholinergic function. The only symptomatic treatment proven effective to date is the use of cholinesterase (ChE) inhibitors to augment surviving cholinergic activity. ChE inhibitors act on the enzymes that hydrolyse acetylcholine (ACh) following synaptic release. In the healthy brain, acetylcholinesterase (AChE) predominates (80%) and butyrylcholinesterase (BuChE) is considered to play a minor role in regulating brain ACh levels. In the AD brain, BuChE activity rises while AChE activity remains unchanged or declines. Therefore both enzymes are likely to have involvement in regulating ACh levels and represent legitimate therapeutic targets to ameliorate the cholinergic deficit. The two enzymes differ in location, substrate specificity and kinetics. Recent evidence suggests that BuChE may also have a role in the aetiology and progression of AD beyond regulation of synaptic ACh levels. Experimental evidence from the use of agents with enhanced selectivity for BuChE (cymserine, MF-8622) and ChE inhibitors such as rivastigmine, which have a dual inhibitory action on both AChE and BuChE, indicate potential therapeutic benefits of inhibiting both AChE and BuChE in AD and related dementias. The development of specific BuChE inhibitors and the continued use of ChE inhibitors with the ability to inhibit BuChE in addition to AChE should lead to improved clinical outcomes.
The cholinergic hypothesis was initially presented over 20 years ago and suggests that a dysfunction of acetylcholine containing neurons in the brain contributes substantially to the cognitive decline observed in those with advanced age and Alzheimer's disease (AD). This premise has since served as the basis for the majority of treatment strategies and drug development approaches for AD to date. Recent studies of the brains of patients who had mild cognitive impairment or early stage AD in which choline acetyltransferase and/or acetylcholinesterase activity was unaffected (or even up-regulated) have, however, led some to challenge the validity of the hypothesis as well as the rationale for using cholinomimetics to treat the disorder, particularly in the earlier stages. These challenges, primarily based on assays of post mortem enzyme activity, should be taken in perspective and evaluated within the wide range of cholinergic abnormalities known to exist in both aging and AD. The results of both post mortem and antemortem studies in aged humans and AD patients, as well as animal experiments suggest that a host of cholinergic abnormalities including alterations in choline transport, acetylcholine release, nicotinic and muscarinic receptor expression, neurotrophin support, and perhaps axonal transport may all contribute to cognitive abnormalities in aging and AD. Cholinergic abnormalities may also contribute to noncognitive behavioral abnormalities as well as the deposition of toxic neuritic plaques in AD. Therefore, cholinergic-based strategies will likely remain valid as one approach to rational drug development for the treatment of AD other forms of dementia.
The discovery of cholinergic deficit in Alzheimer's disease (AD) patient's brain has triggered research efforts, using cholinomimetic approaches for their efficacy in AD therapy. Various therapies may be of potential clinical use in AD. Among these are cholinergic agents, which include muscarinic agonists, acetylcholinesterase inhibitors, and acetylcholine releasing agents. One of the muscarinic agonists tested in AD is arecoline and its bioisosters, which are widely explored as muscarinic receptor 1 agonist (M1 receptor agonist) in AD research. In this regard, five-membered heterocyclic ring system attached arecoline basic nucleus (N-methyl tetrahydropyridines) at third position has been extensively researched on. The present research involved synthesis of arecoline thiazolidinones 5(a-j) by using dipolar addition of 3-aminopyridine and alkyl/aryl carboxaldehydes in presence of gamma ferrite as catalyst. The resulting products were methylated and reduced to get desired products. Subsequently the synthesized arecoline thiazolidinones were subjected to in vitro muscarinic receptor binding studies using male Wistar rat brain (cerebral cortex) membrane homogenate and extended this in vitro study to in vivo pharmacological evaluation of memory and learning in male Wistar rats. Four derivatives (5a-5c and 5e) showed considerable M1 receptor binding affinity (in vitro) and elicited beneficial effects in vivo memory and learning models (Rodent memory evaluation, plus and Y maze studies).
Ameliorative effect of novel vitamin formula with herbal extracts on scopolamine-induced alzheimer's disease
- M L Jeong
- S Sandesh
- Jae Wp Noh
- I C Woon
- D C Jung
Jeong ML, Sandesh S, Jae WP. Noh IC, Woon DC, Jung HC.
Ameliorative effect of novel vitamin formula with herbal extracts on
scopolamine-induced alzheimer's disease. Asian J Pharm Clin Res
2013;6(2):175-9.