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 influence of nondepolarizing muscle relaxants (MR) on the resting and electrically evoked release of tritiated norepinephrine (3H-NE) was investigated, in the absence and presence of 10(-4) mol/l cocaine, in the in vitro right atrium preparation of guinea pigs (g.p.) preloaded with 3H-NE. In the absence of MR both resting and stimulated 3H and 3H-NE release remained relatively constant throughout the experiment and the ratios of the evoked release of 3H during consecutive stimulation periods (i.e. S2/S1, S3/S2) were close to unity. None of the MR had any effect on resting 3H release. Atropine (3 x 10(-7) mol/l), gallamine (7 x 10(-5) mol/l), and pancuronium (2 x 10(-6) mol/l), but not d-tubocurarine (5 x 10(-6) mol/l) significantly increased stimulated release of 3H-NE. The effect of MR on resting or evoked release of 3H-NE was not influenced by 10(-4) mol/l cocaine. In the presence of atropine gallamine and pancuronium did not affect the release of 3H-NE. This finding indicates that the effect of MR was mediated via presynaptic muscarinic receptors. Muscle relaxants and atropine inhibited these receptors and removed the tonic inhibitory effect of acetylcholine (ACh) released from the parasympathetic nerve endings on the release of NE from the sympathetic nerve. This was substantiated by the finding that in the present of cholinesterase inhibition, when the effect of endogenous ACh was amplified and thereby the cholinergic tone was dominant, the total release of 3H-NE evoked by stimulation was much lower and muscle relaxants and atropine were much more effective to enhance 3H-NE release. Gallamine and pancuronium also increased the force of contraction of the electrically stimulated atria. These findings indicate that the acceleration of the heart rate observed with gallamine and pancuronium in anesthetized man is due to increased release from, and not the inhibition of reuptake of NE by the sympathetic nerve endings of the right atrium.
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PMID:Presynaptic effect of muscle relaxants on the release of 3H-norepinephrine controlled by endogenous acetylcholine in guinea pig atrium. 252 77

The binding of [3H]quinuclidinyl benzilate ([3H]QNB) to cardiac muscarinic receptors was inhibited not only by classical muscarinic antagonists but also by nicotinic blocking agents and inhibitors of acetylcholinesterase. Gallamine, pancuronium, ambenonium, and decamethonium were the most potent of these agents examined. All of the nicotinic antagonists with significant muscarinic receptor activity had two or three quaternary nitrogens, and the potency of a series of these compounds was a function of the distance between quaternary nitrogens. The effects of gallamine and pancuronium were studied in detail because these neuromuscular blocking agents showed heterogeneity in their binding to cardiac muscarinic receptors, whereas classical muscarinic antagonists such as QNB and atropine did not. Gallamine did not compete for all of the [3H]QNB binding sites on atrial membranes, but left at least 20% of [3H]QNB binding unaffected. Curves of pancuronium competition for [3H]QNB binding were shallow, consistent with two binding sites for pancuronium, with approximately 20% having low affinity. Additionally, in the presence of gallamine or pancuronium, [3H]QNB binding sites were no longer homogeneous, and Scatchard plots became nonlinear. Guanine nucleotides did not alter the effect of gallamine or pancuronium on [3H]QNB binding. Gallamine and pancuronium showed no agonist activity but, like atropine, completely antagonized muscarinic receptor-mediated inhibition of cyclic AMP formation. However, differences in the behavior of gallamine and atropine suggested that gallamine was not a purely competitive antagonist. Gallamine did not protect against receptor alkylation by propylbenzilylcholine mustard, and [3H]QNB dissociation was apparently slowed by gallamine. We interpret our data to suggest that gallamine not only competes for [3H]QNB binding sites, but also binds at a secondary site on the receptor, forming a ternary complex with [3H]QNB. Heterogeneity in ligand binding is proposed to result from the dual actions of gallamine and pancuronium as ligands at both primary and secondary sites on the cardiac muscarinic receptor.
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PMID:Heterogeneity of binding sites on cardiac muscarinic receptors induced by the neuromuscular blocking agents gallamine and pancuronium. 613 50

Systemically administered cholinomimetics or cholinesterase inhibitors can depress behavior in humans and animals, whereas antimuscarinic agents reverse this effect or even produce euphoria. Although these effects have been well documented, the specific brain regions that mediate them remain largely unknown. In the present experiments, muscarinic agonists and antagonists were locally injected into the nucleus accumbens of female Sprague-Dawley rats to test for their effects on behavioral depression in the Porsolt swim test and locomotor activity. Local, microinjections of the drugs in the accumbens elicited behaviors that were similar to the systemic effects reported in other studies. Injection of the non-specific agonist arecoline (40 and 80 microg) dose-dependently inhibited swimming and escape behavior. This may be mediated in part by accumbens M1 receptors because blocking these receptors with the specific antagonist pirenzepine (17.5 and 35.0 microg) did the opposite by increasing swimming. Gallamine (0.13, 0.44, and 0.88 microg), an antagonist at M2 receptors, dose-dependently decreased swimming. Two-way microdialysis suggested that this was in part due to the release of ACh by blocking M2 autoreceptors. Scopolamine, a mixed M1/M2 receptor antagonist, also released ACh but did not decrease swimming, probably because the M1 receptors were blocked; the drug (1.0 microg) increased swimming time, much like pirenzepine. With the exception of arecoline, none of the drugs significantly affected locomotor activity in a photocell cage. Arecoline (40 microg), which had decreased swimming, reduced activity. The present study suggests that muscarinic receptors in the nucleus accumbens can control immobility in the Porsolt swim test. The onset of immobility may depend on the activation of post-synaptic M1 receptors.
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PMID:Nucleus accumbens muscarinic receptors in the control of behavioral depression: antidepressant-like effects of local M1 antagonist in the Porsolt swim test. 1144 Aug 10

The aim of the study was to analyse in a well-established model of neophobia the effects of peripheral and central (ICV) administration of a prototypical and easily penetrating to the brain acetylcholinesterase inhibitor (AChE-I)--physostigmine, hemicholinium, a selective blocker of the high affinity choline uptake sites, as well as muscarinic and nicotinic receptor ligands. Thus, an attempt was made to address the question whether anxiolytic-like effects of AChE-I, reported in the clinic, are directly related to the anti-emotional action. The effects of peripherally and centrally administrated cholinergic ligands on novelty-induced decrease in exploratory behaviour were examined in rats. It was found that in a limited dose-range physostigmine and nicotine given peripherally or ICV selectively disinhibited rat exploration in the open field, whereas scopolamine stimulated animal motor activity and increased thigmotaxis. Locomotor effects of physostigmine and nicotine appeared at the higher doses and could be easily separated from their anti-neophobic action. The rat's exploratory behaviour tended to be attenuated by central administration of hemicholinium (a choline uptake blocker), and it was significantly inhibited by mecamylamine (a nicotinic receptor antagonist), and pirenzepine (a selective M1 receptor antagonist). Gallamine, a selective M2 receptor antagonist, did not influence on animal novelty-induced anxiety-related behaviour. It is concluded that AChE-I can selectively affect brain emotional processes evoked by neophobia-related stimuli. Probably both nicotinic and M1 cholinergic receptors mediate such an action of AChE-I.
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PMID:The effects of physostigmine and cholinergic receptor ligands on novelty-induced neophobia. 1145 93

Gallamine and tacrine are allosteric antagonists at muscarinic M2 acetylcholine receptors and inhibitors of acetylcholinesterase. At both acetylcholine-binding proteins, gallamine and tacrine are known to occupy two different binding sites: in M2 receptors within the allosteric binding area and in acetylcholinesterase at its catalytic and its peripheral site. To find new ligands of both targets, we designed a gallamine-tacrine dimer and several derived hybrid compounds to address the two binding sites. Their M2 receptor allosteric and acetylcholinesterase inhibitory potential was determined. The hybrid compounds revealed an allosteric potency in the low nanomolar range exceeding the allosteric potency of gallamine and tacrine by factors of 100 and 4800, respectively. Cholinesterase inhibition was augmented by hybrid formation, and all compounds exhibited IC50 values in the lower nanomolar range. Thus, gallamine-tacrine hybrid formation is a valuable approach toward high affinity ligands concurrently targeting these acetylcholine-binding proteins.
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PMID:First gallamine-tacrine hybrid: design and characterization at cholinesterases and the M2 muscarinic receptor. 1794 54

Esters of dimethylcarbamic acid are known to be poor substrates of acetylcholinesterase. They carbamylate the active catalytic site of the enzyme and the subsequent decarbamylation is a slow but measurable process. Similarly, acetylcholinesterase can be phosphonylated, and the dephosphonylation is extremely slow. Rapid hydrolysis of phosphonylated acetylcholinesterase can be brought about by oximes, but dealkylation of the phosphonyl group on the enzyme (known as ageing) renders the inhibited enzyme insensitive to oximes. In the present work, decarbamylation of dimethylcarbamyl-acetylcholinesterase and ageing of isopropylmethylphosphonyl-acetylcholinesterase were studied at a physiological ionic strength (154 mM). Gallamine, d-tubocurarine and alcuronium accelerated reactivation of dimethylcarbamyl-acetylcholinesterase. Gallamine and tubocurarine enhanced the effect of the nucleophile 3,3-dimethyl-1-butanol on decarbamylation, and the interaction was synergistic in the case of gallamine. Gallamine and tubocurarine retarded ageing of isopropylmethylphosphonyl-acetylcholinesterase, whereas 3,3-dimethyl-1-butanol had no effect. Nevertheless 3,3-dimethyl-1-butanol enhanced the retarding effects of gallamine and tubocurarine. All these effects, except the effects of 3,3-dimethyl-1-butanol on ageing, had been previously observed at low ionic strength, in which case the effects were more marked and were observed at lower concentrations of the drugs. The effects at low ionic strength have been attributed to binding of the drugs to a peripheral site on the enzyme with a consequent change in conformation at the active site, leading to altered kinetic properties. The present results suggest that such allosteric effects may persist at physiological ionic strength. There have been few indications previously that this is so, particularly in the case of solubilised acetylcholinesterase.
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PMID:Gallamine and tubocurarine as possible allosteric modifiers of soluble acetylcholinesterase activity at physiological ionic strength. 2048 40

Gallamine and tubocurarine increased the rate of decarbamylation of carbamylated Triton-solubilized rabbit brain acetylcholinesterase and interacted synergistically with 3,3-dimethyl-1-butanol in the acceleration of decarbamylation at low ionic strength. Gallamine and tubocurarine also accelerated decarbamylation at a physiological ionic strength, but in this case the interaction with 3,3-dimethyl-1-butanol was not synergistic. Tubocurarine decreased the rate of ageing of isopropylmethyl-phosphonyl-acetylcholinesterase at low ionic strength, but gallamine and tubocurarine had no effect on ageing at a physiological ionic strength, nor did gallamine at low ionic strength. However reductions in the rate of ageing were observed for gallamine/3,3-dimethyl-1-butanol and tubocurarine/3,3-dimethyl-1-butanol mixtures at low ionic strength. Gallamine increased the maximum velocity of hydrolysis of acetylthiocholine at low ionic strength, but not at physiological ionic strength. Gallamine increased the rate of carbamylation of acetylcholinesterase by physostigmine and neostigmine at low ionic strength; however the data were not consistent with a simple model of complexing inhibition by these carbamates. Overall, the kinetic properties of Triton-solubilized rabbit brain acetylcholinesterase were less sensitive to modification by proposed allosteric effectors than bovine erythrocyte acetylcholinesterase, the allosteric properties of which have been reported previously, and millimolar concentrations of gallamine and tubocurarine were required to produce observable effects at physiological ionic strength. Further experiments are required to determine whether acetylcholinesterase is similarly insensitive to allosteric regulation in vivo.
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PMID:Modification of the kinetic properties of Triton-solubilized rabbit brain acetylcholinesterase by allosteric effectors at low ionic strength. 2050 64

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