Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.7 (acetylcholinesterase)
28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The present study investigated the effects of tacrine (an inhibitor of acetylcholinesterase) and zacopride (the antagonist of 5-HT3 receptors) on the performance of adult rats in a continuous operant delayed non-matching to position task assessing spatial working memory. 2. Adult rats had a decline in the percent correct responses at the longest delays (16 and 30 sec) in this task. Tacrine (1.0 mg/kg) or zacopride (0.0025, 0.05, 1.0 mg/kg) did not increase the percent correct responses at any time delays. The higher dose of tacrine reduced behavioural activity (e.g. the decreased number of trials completed and increased sample press latency) of rats during memory testing, and it slightly increased choice accuracy across all the delays. 3. The combination of zacopride (1.0 mg/kg) and tacrine (1.0 mg/kg) increased the percent correct responses at the shortest delays, but not at the longest delays. 4. These results indicate a non-mnemonic improvement in the accuracy performance of rats, and they suggest that the effects of acute, systemic administrations of zacopride (which is thought to increase the release of acetylcholine) or/and tacrine (which inhibits the breakdown of acetylcholine) do not improve spatial working/short-term memory in rats.
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PMID:The effects of tacrine and zacopride on the performance of adult rats in the working memory task. 836 50

Clinical Alzheimer disease (AD) is a heterogeneous disorder, and it is possible to subgroup patients by a number of different criteria. One such subgrouping is those who have a positive response to cholinergic therapy and those who do not. This phenomenon has been clearly recognised in a number of therapeutic trials of cholinesterase inhibitors and is likely to be an issue in clinical practice. Tacrine, the first cholinesterase inhibitor to be approved for the treatment of AD, has, at best, modest effects on 20-50% of patients and is associated with a high frequency of side effects, including liver transaminitis. The potential of clinical tests or other investigations to identify those patients who are more likely to respond to cholinergic therapy would be a valuable aid in the clinical use of these therapies. In this article we review the issue of heterogeneity in patient populations, in the design of trials and in the pharmacological compounds used in trials. We then summarise the findings of a number of small studies of potential response predictors, which include the use of psychometric tests, orthostatic blood pressure, pupillary dilation, the electroencephalogram, cerebrospinal fluid neurochemistry, and techniques involving functional imaging. Although some results are promising, generalisability is limited by the small numbers of patients studied and the frequent open nature of the designs used. The main conclusion that can be drawn is that adequate doses are required to achieve therapeutic plasma levels before nonresponse is accepted.
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PMID:Clinical heterogeneity: responders to cholinergic therapy. 853 22

The pharmacological properties of MKC-231 (2-(2-oxopyrrolidin-1-yl)-N- (2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl) acetoamide, CAS 135463-81-9) in comparison with an acetylcholinesterase (AChE) inhibitor, tacrine (CAS 1684-40-8) were studied. MKC-231(10(-10)-10(-6) moll) significantly increased high affinity choline uptake (HACU) when it was incubated with the hippocampal synaptosomes of ethylcholine mustard aziridinium ion (AF64A) treated rats, but not of normal rats. MKC-231 did not affect the AChE activity, [3H]- quinuclidinyl benzilate binding, and [3H]-pirenzepine binding. Oral administration of MKC-231 (1-10 mg/kg) significantly improved the learning deficits in the Morris' water maze of AF64A-treated rats, but it did not produce any significant side effects, like tremor, salivation or hypothermia, which were observed in rats treated with high doses of tacrine. Tacrine (0.1-3 mg/kg p.o.) failed to ameliorate the learning deficits in AF64A-treated rats. These results suggest that MKC-231 is a novel and quite unique compound, which improves the memory impairment induced by AF64A through the enhancement of HACU without any side effects at the effective doses.
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PMID:Effect of the novel high affinity choline uptake enhancer 2-(2-oxopyrrolidin-1-yl)-N-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b] quinolin-4-yl)acetoamide on deficits of water maze learning in rats. 874 80

Tacrine [1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate (THA), Cognex] is a potent acetylcholinesterase inhibitor recently approved for treatment of mild-to-moderate Alzheimer's disease. The potential for THA and/or a metabolite of THA to accumulate in brain tissue was investigated by autoradiographic and metabolic profiling techniques in rats given single and multiple doses of [14C]THA. In addition, the brain-to-plasma distribution time course of orally administered 1-hydroxy-THA (1-OH-THA, 24 mg/kg), a primary rat metabolite with anticholinesterase activity, was also examined. Results from a 16 mg/kg single-dose study showed THA to cross the blood-brain barrier readily and concentrate in brain tissue, approximately 5-fold compared with plasma. The metabolite 1-OH-THA was found in much lower amounts relative to THA and when given separately at a similar dose the levels in brain tissue were comparable with plasma concentrations. After multiple-dose administration, THA concentrations in brain tissue were approximately 3-fold higher than those achieved after a single oral dose. However, concentration of 1-OH-THA metabolite increased only 50%. These data suggest a marked difference between the ability of THA and 1-OH-THA to accumulate in brain tissue and may reflect differences in lipophilicity as estimated by calculated log p values. The relevance of THA accumulation in brain tissue to delays observed in THA clinical management of Alzheimer's disease remains to be established.
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PMID:Distribution of tacrine and metabolites in rat brain and plasma after single- and multiple-dose regimens. Evidence for accumulation of tacrine in brain tissue. 878 77

Tacrine is the first drug approved for the treatment of Alzheimer's disease. Approximately 50% of patients treated with tacrine develop elevated serum aminotransferase levels, as an indication of potential hepatotoxicity. However, acute and chronic studies with a limited number of animal models have not demonstrated hepatotoxicity. The present study compared the cytotoxicity in hepatocyte cultures of tacrine with structurally (proflavine and 9-aminoacridine) or pharmacologically similar compounds (physostigmine), as well as structurally modified tacrine to determine if there was a structure activity relationship with regards to toxicity. Cytotoxicity was assessed by determination of extra- and intracellular amounts of lactate dehydrogenase. Cytotoxicity was assessed after a four-hour exposure over a test compound concentration range of 0 to 3 mM. Concentration-dependent cytotoxicity occurred with tacrine and all structurally related compounds. Physostigmine which is pharmacologically similar, but structurally different, did not induce cytotoxicity. Cytotoxic potency did not appear to be related to acetylcholinesterase inhibitory activity, while compounds with acridine structures induced cytotoxicity. Thus, in this in vitro model, cytotoxicity appears to be related to structure and not pharmacological action. Results of this study indicate that compounds structurally related to tacrine are cytotoxic because of the heterocyclic ring structure. Neither unsaturation of an aromatic ring of the heterocyclic compound, amino substitution of the heterocyclic rings, N-hydroxylation of the amino group, nor ring hydroxylation dramatically alter cytotoxicity.
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PMID:Cytotoxicity study of tacrine, structurally and pharmacologically related compounds using rat hepatocytes. 880 54

Rat cortical synaptosomes preloaded with [3H]choline were superfused and stimulated with K+ in order to investigate the effect of the cholinesterase inhibitor tacrine on the in vitro release of acetylcholine (ACh). Tacrine was found to biphasically both increase (10(-6) and 5 x 10(-6) M) and decrease (10(-5)-10(-4) M) the release of ACh in a concentration-dependent manner. The facilitatory effect of tacrine was prevented by atropine and the M1 antagonist pirenzepine, whereas the inhibitory effect induced by tacrine was blocked by atropine and the M2 antagonist AF-DX 116. These results indicate that tacrine causes a biphasic effect on K+ stimulated ACh release in the brain via M1 and M2 muscarinic receptors. The tacrine induced enhancement of the ACh release occurs at clinical relevant tacrine concentrations and might therefore be of importance for the treatment outcome of Alzheimer's disease.
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PMID:Biphasic effect of tacrine on acetylcholine release in rat brain via M1 and M2 receptors. 883 62

Alzheimer's disease (AD) is a neurodegenerative disorder with impairment of cognitive function and personality. The synaptic loss, neuronal atrophy and degeneration of cholinergic nuclei in the basal forebrain may be associated with a reduction in oxidative metabolism of glucose, a fall in acetyl CoA and ATP. Current pharmacological strategies, aimed at increasing cholinergic activity include acetylcholinesterase (AChE) inhibitors, cholinergic agonists, acetylcholine (ACh) releasers and stimulants of nerve growth factors (NGF). AChE inhibitors, physostigmine and Tacrine can slow the decline of cognitive function and memory in some patients with mild or moderate AD, if given for at least 3-6 months in sufficient doses to inhibit brain AChE. Their main disadvantages are low oral bioavailability, peripheral cholinergic hyperactivity and liver toxicity with Tacrine. Newer, less toxic AChE inhibitors, with selective central activity, formulations of physostigmine, selective Ml and nicotinic agonists are becoming available with improved bioavailability and pharmacokinetics. These may increase the likelihood of therapeutic benefit in AD. Nootropic drugs, e.g. piracetam, which release ACh and are relatively non-toxic could possibly slow the progression of the disease. A combination of an AChE inhibitor, piracetam and a stimulator of NGF may show additive effects on memory processes but with a lower incidence of untoward effects.
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PMID:The pharmacotherapy of Alzheimer's disease based on the cholinergic hypothesis: an update. 884 27

The effect of chronic treatment with the cholinesterase inhibitor tacrine on alpha 4 beta 2 nicotinic acetylcholine receptors (nAChRs) was investigated in a transfected fibroblast cell line, M10. Tacrine significantly increased (+46%; 5 x 10(-8) to 10(-5) M) and decreased (-74%; 2 x 10(-5) to 10(-4) M) the number of nAChRs in the M10 cells in a concentration-dependent manner when using [3H]cytisine as labelled ligand. The mRNA levels for alpha 4 or beta 2 nAChR subunits remained unchanged following the treatment. The tacrine-induced increase in number of nAChRs was significantly blocked by the antagonist mecamylamine (10(-4) M), while tubocurarine (10(-4) M) had no effect. Neither of the antagonists prevented the decrease in the number of nAChRs obtained at the higher concentration of tacrine. Similar to nicotine, tacrine (5 x 10(-5) M) decreased the turnover rate of nAChRs, which might indicate neuroprotective properties. This study demonstrates that tacrine interacts with two sites on nAChRs, where activation of the noncompetitive allosteric site might contribute to the clinical efficacy of tacrine treatment in AD patients.
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PMID:Tacrine interacts with an allosteric activator site on alpha 4 beta 2 nAChRs in M10 cells. 893 Sep 89

Tacrine, the first drug specifically approved for Alzheimer's disease, produces symptomatic improvement. The theoretical rationale behind treating Alzheimer's disease with tacrine is based on central cholinergic depletion. Tacrine is centrally acting, uncompetitive reversible inhibitor of acetylcholinesterase and butyrylcholinesterase. Multiple clinical trials support the effectiveness of tacrine in Alzheimer's disease. High dosages of tacrine are required for efficacy, with the potential for hepatic and mild gastrointestinal adverse effects. However, the benefits of tacrine currently outweigh its risks, and a trial of the drug should be offered to patients. As clinical experience with tacrine increases, the long term risk-benefit equation may be refined.
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PMID:A risk-benefit assessment of tacrine in the treatment of Alzheimer's disease. 901 Jun 44

We examined the neurochemical effects of 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-benzaze pin-8-yl)-1-propanone fumarate (TAK-147), a novel acetylcholinesterase (AChE) inhibitor in vitro and in vivo. TAK-147 showed a potent and reversible inhibition of AChE activity in homogenates of the rat cerebral cortex (IC50 = 51.2 nM), and was 3.0- and 2.4-fold more potent than tacrine and physostigmine, respectively. By contrast, TAK-147 was the least potent inhibitor of butyrylcholinesterase activity in rat plasma (IC50 = 23,500 nM). Tacrine and physostigmine inhibited butyrylcholinesterase activity potently and nonselectively. TAK-147 showed a moderate inhibition of muscarinic M1 and M2 receptor binding with K(i) values of 234 and 340 nM, respectively. TAK-147 showed very weak or no inhibition of high-affinity choline uptake, nicotinic receptor binding and choline acetyltransferase activity. In ex vivo experiments, oral administration of TAK-147 at doses ranging from 1 to 10 mg/kg induced a statistically significant and dose-dependent decrease in AChE activity in the cerebral cortex. Of the monoaminergic systems, TAK-147 moderately inhibited uptake of noradrenaline and serotonin with IC50 values of 4020 and 1350 nM, respectively. TAK-147 also inhibited ligand binding at alpha-1, alpha-2 and serotonin 2 receptors with K(i) values of 324, 2330 and 3510 nM, respectively, whereas it showed only weak activities on D1, D2 and serotonin 1A receptor bindings. Oral administration of TAK-147 (3 mg/kg) significantly accelerated the turnover rates of dopamine, noradrenaline and serotonin in the rat brain. These results suggest that TAK-147 activates the central cholinergic system by specific inhibition of AChE activity without affecting peripheral butyrylcholinesterase activity, and that TAK-147 also moderately activates the monoaminergic systems.
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PMID:Neurochemical effects of 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-b enzazepin-8-yl)-1-propanone fumarate (TAK-147), a novel acetylcholinesterase inhibitor, in rats. 906 12


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