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)

The effect of galanthamine, tacrine, and oxazyl (ambenomum) on human red cells acetylcholinesterase phosphorylation by armine and Gd-42 (o-ethyl-s-beta-ethylthioethyl ester of methylthiophosphinic acid) was studied. In the presence of galanthamine phosphororganic inhibitors interacted only with the active center of the enzyme, the anionic site of which was not occupied by the reversible inhibitor. Tacrine and oxazyl decreased the reactivity of the free enzyme and the rate of its phosphorylation.
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PMID:[Effect of reversible inhibitors on the reaction capacity of functional portions of the active center of acetylcholinesterase]. 70 73

We administered 9-amino-1,2,3,4-tetrahydroacridine (THA, Tacrine) to mice in doses (0.3-3 mg/kg) which have been shown to enhance cognition. Animals were sacrificed at various time points and several markers of cholinergic function were measured. Following 3 mg/kg THA, drug levels in brain were sufficient to inhibit 78-80% of brain acetylcholinesterase activity, regardless of treatment duration. However, repeated administration of THA did not alter the number of muscarinic receptors or the phosphoinositide response to muscarinic receptor agonists. Thus, at therapeutically relevant doses, THA inhibits the activity of brain acetylcholinesterase substantially, but does not affect the density of muscarinic receptors on their ability to activate second messenger systems. These results are in contrast to those obtained by other investigators who found significant decreases in muscarinic receptor number following chronic administration of higher doses of THA.
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PMID:Muscarinic receptor function and acetylcholinesterase activity after chronic administration of tacrine to mice at therapeutic drug concentrations. 131 62

The effects of tacrine (5 mg/kg i.p.), a potent acetylcholinesterase inhibitor, were studied in rats pretreated (24 h beforehand) with a single dose (12 mEq/kg i.p.) of LiCl. Tacrine and LiCl were ineffective when given individually. Tacrine elicited seizures and brain damage in 90% of the rats treated. The intracerebroventricular microinfusion of N omega-nitro-L-arginine methyl ester (300 micrograms given 24 h after LiCl administration) significantly reduced the seizures and brain damage produced by tacrine (given 15 min later). These experiments suggest that the seizures and brain damage elicited by tacrine may be due, in part, to increased nitric oxide production in the brain.
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PMID:Tacrine-induced seizures and brain damage in LiCl-treated rats can be prevented by N omega-nitro-L-arginine methyl ester. 132 16

Tacrine is a cholinesterase inhibitor with activity in the central nervous system originally marketed for the reversal of competitive neuromuscular blockade. Because a marked reduction in cholinergic neurons is a hallmark of brain changes in Alzheimer disease, tacrine has been studied in two placebo-controlled clinical trials of patients with probable Alzheimer disease. Standard analysis of variance (ANOVA) and analysis of covariance (ANCOVA) have shown a difference between the tacrine group and the placebo group in terms of the cognitive component of the Alzheimer disease assessment scale at the end of the placebo-controlled phase. Due to limitations of ANOVA and ANCOVA, only a selected group of patients could be analyzed by those methods. A population pharmacodynamic model has been developed that allows the use of all observations from one or more trials to be combined. It can incorporate any sequence of active or placebo treatments and account for carryover effects of both placebo and active drug. The time courses of active or placebo treatment response and the development of tolerance to active drug or placebo can be defined. The model describes disease progression without treatment, the placebo effect, and the effect of tacrine as a function of daily dose. Placebo effect and active drug effects are modeled by effect site concentration components.
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PMID:Methodologic aspects of a population pharmacodynamic model for cognitive effects in Alzheimer patients treated with tacrine. 145 35

Three patients with Alzheimer's disease, a 68-year-old woman with mild dementia and 2 men (aged 64 and 72 years) with moderate dementia were treated orally with the cholinesterase inhibitor tacrine (tetrahydroaminoacridine), 80 mg daily, for several months. The patients were investigated using positron emission tomography (PET) prior to, and after 3 weeks and 3 months of treatment. The PET studies involved a multi-tracer system consisting of [18F]-fluoro-deoxy-glucose (18F-FDG) (tracer for glucose metabolism); 11C-butanol (cerebral blood flow) and (S)(-)- and (R)(+)-[N-11C-methyl]-nicotine (nicotinic receptors; cholinergic neural activity). Tacrine treatment increased the uptake of 11C-nicotine to the brain. Significant reduced difference in uptake between the two enantiomers (S)(-)- and (R)(+)11C-nicotine was observed in the frontal and temporal cortices after tacrine treatment in all three patients. The kinetic analysis indicated increased binding of (S)(-)11C-nicotine in brain compatible with a restoration of nicotinic cholinergic receptors. The most pronounced effect was observed after 3 weeks and 3 months treatment in the patient with mild dementia. An increase in cerebral glucose utilization was found in the 68-year-old patient with mild dementia but also slightly in the 64-year-old man with moderate dementia when treated with tacrine for 3 months. Tacrine administration did not affect cerebral blood flow. The PET data obtained after 3 weeks of tacrine treatment was paralleled by improvement in neuropsychological performance. This study shows in vivo by PET neurochemical effects induced in brain by treatment with tacrine to Alzheimer patients. Intervention with tacrine in the early course of the disease might be necessary for clinical improvement.
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PMID:Tacrine restores cholinergic nicotinic receptors and glucose metabolism in Alzheimer patients as visualized by positron emission tomography. 149 41

Amnesia can be induced in rats in the passive avoidance paradigm by administration of scopolamine, a central muscarinic receptor antagonist. Tacrine or galanthamine, inhibitors of acetylcholinesterase, given in conjunction with scopolamine partially reversed the scopolamine-induced deficit in passive avoidance performance. Four so-called cognitive enhancers, all widely used for the treatment of the symptoms associated with mental aging, cerebral insufficiency and senile memory disorder, were investigated in this paradigm. Piracetam, an extract of Ginkgo biloba, dihydroergocristine and a combination of raubasine with dihydroergocristine, all attenuated the amnesia induced by scopolamine. In contrast, nicergoline had no significant effect. Raubasine alone also failed to significantly attenuate scopolamine-induced amnesia, although some doses of raubasine had a non-significant tendency (P less than 0.10) to reduce the amnesia.
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PMID:Effects of four non-cholinergic cognitive enhancers in comparison with tacrine and galanthamine on scopolamine-induced amnesia in rats. 173 91

THA (Tacrine), a drug used in the experimental therapy of dementia of Alzheimer's disease type, and whose biochemical site of action is believed to be the neural cholinesterase, is shown, for the first time, to be an immunosuppressant in vitro on normal human peripheral blood lymphocytes in microgram quantities. THA down-regulates non-MHC restricted natural killer (NK) cell activity without affecting the general viability of cells. This down-regulation can be demonstrated at all effector and target (K562) concentrations, in purified resting NK cells as well as in lymphokine (interleukin 2) activated killer cells in 3- or 16-h NK assays and in all the blood samples tested. Kinetic analysis shows that the Vmax (maximal cytotoxic potential) and Km of NK cell-mediated cytolysis are also attenuated. Single cell assays using agarose matrix reveal that THA moderately interferes with tumor target binding/recognition events and strongly abrogates the delivery of lethal hit, thus lowering the frequency of active killer cells among THA-treated lymphocytes. THA down-regulates NK cells upon direct interaction and does not require the help of non-NK cells. The THA sensitive site(s) on NK cells does not appear to be perturbed significantly either by their proliferative status or by membrane modulations that may be normally induced by interleukin 2. The in vitro immunomodulatory pharmacological properties of THA reveal that the biological site of action of THA extends to non-neural cells also. Such non-neural models may be helpful in exploring the pathophysiological neuroimmunomodulatory properties of THA at cellular and molecular levels.
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PMID:Immunomodulation by 9-amino-1,2,3,4-tetrahydroacridine (THA): 1. Down-regulation of natural cell-mediated cytotoxicity in vitro. 176 1

Decarbamylation rate of membrane-bound methyl- and dimethyl-carbamylated acetylcholinesterase of human erythrocytes and bovine brain is reliably 1.1-1.6 times lower than that of the soluble enzyme. Such reversible inhibitors as tacrine (of non-competition action), ambenonium (mixed action) and galanthamine (competitive type of action) decelerate the decarbamylation rate of acetylcholinesterase. At pH 6 tacrine inhibits the reduction rate of soluble acetylcholinesterase activity of human erythrocytes more intensively than that of membrane-bound acetylcholinesterase. No differences in decarbamylation rate were found for the both forms of the enzyme at pH 8. Tacrine, a non-competitive inhibitor in concentrations below the inhibition constant (Ki = 1.4 x 10(-7) M) exerts the most intensive effect on the decarbamylation rate of methyl- and dimethylcarbamylated acetylcholinesterase of the mouse brain, while ambenonium and galanthamine in concentrations much (tens times) exceeding their Ki (3.1 x 10(-10) M and 4.4 x 10(-7) M, respectively) provide a decrease of the decarbamylation rate.
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PMID:[The effect of pH and reversible inhibitors on decarbamylation of acetylcholinesterase]. 192 83

Tacrine (THA) is a potent cholinesterase inhibitor being studied for the treatment of Alzheimer's disease. The metabolism and excretion of THA were studied in rats following a single oral dose of 20 mg/kg of THA. The results show THA was extensively metabolized in rats after oral administration. Three major urinary metabolites were isolated by HPLC on a semi-prep analytical phenyl column, and subsequent purification of the individual fractions on a semi-prep analytical cyano column. The major metabolic pathways involve the hydroxylation of the saturated ring at positions 1, 2, and 4. The structures of the metabolites 9-amino-1,2,3,4-tetrahydroacridin-1-ol (1-OH-THA), 9-amino-1,2,3,4-tetrahydroacridin-2-ol (2-OH-THA), and 9-amino-1,2,3,4-tetrahydroacridin-4-ol (4-OH-THA) were determined by electron impact mass spectrometry and/or 1H-NMR, and compared with synthetic references. The urinary excretion of THA and metabolites was quantitated by HPLC with UV detection. About 60% of the oral dose was eliminated as total THA, 1-OH-THA, 2-OH-THA, and 4-OH-THA over a 48-hr collection interval; and the non-conjugated THA and hydroxylated metabolites accounted for 45% of the dose.
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PMID:Identification of the urinary metabolites of tacrine in the rat. 198 36

Tetrahydroaminoacridine (THA; Tacrine) is a potent, non-competitive inhibitor of the neuronal enzyme acetylcholinesterase (AChE) and, consequently, a potent modulator of central cholinergic function. The compound reportedly improves the memory deficits of Alzheimer's dementia. Experiments were run with purified bovine caudate AChE to examine the kinetic properties of THA-AChE interaction within the scheme of multiple binding sites on the enzyme and a proposed "map" of the enzyme surface. The kinetic analyses were also designed to determine whether chemical modification of peripheral anionic sites on AChE may provide insight into mechanism for selective pharmacological alteration of cholinergic function in the brain. The studies demonstrated that THA is a reversible, non-competitive inhibitor with an I50 of 160 +/- 10 nM. THA bound primarily at a hydrophobic area outside of the catalytic sites, and binding of THA enhanced the effect of Ca2+ binding to a separate group of "accelerator" sites. Experiments with Al3+ demonstrated non-competitive inhibitor effects that were additive with THA inhibition and consistent with a model suggesting interaction of THA and Al3+ at the enzyme surface. In vitro enzyme inhibition studies also provide evidence for THA "protection" of the catalytic site against inhibition by the high-affinity phosphorylating agent, DFP (isoflurophate).
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PMID:Pharmacological significance of acetylcholinesterase inhibition by tetrahydroaminoacridine. 239 Jan 4


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