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)

Three sigma receptor ligands were examined for their ameliorating effects on p-chloroamphetamine-induced amnesia in mice. p-Chloroamphetamine was administered intraperitoneally 30 min before the training session of the passive avoidance response. Each sigma receptor ligand was administered 60 min before or immediately after the training session, or 60 min before the retention test. (+)-N-Allylnormetazocine ((+)-SKF-10,047), a prototype benzomorphan sigma receptor ligand, significantly reduced the p-chloroamphetamine-induced amnesia in these three administration schedules, as do acetylcholinesterase inhibitors. On the contrary, the significant anti-amnesic effects elicited by non-benzomorphan sigma receptor ligands, 1,3-di-(2-tolyl)guanidine (DTG) or (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperizine ((+)-3-PPP), were observed depending upon the timing of their administration. In addition, the ameliorating effect of (+)-SKF-10,047 against the p-chloroamphetamine-induced amnesia was superior to that of (-)-SKF-10,047. The (+)-SKF-10,047-induced anti-amnesic effect was significantly antagonized by the concurrent administration of either scopolamine, a muscarinic receptor antagonist, or hemicholinium-3, an inhibitor of the Na(+)-dependent high-affinity choline uptake site. These findings indicated that sigma receptor ligands had anti-amnesic effects against drug-induced memory impairment. In addition, the anti-amnesic effect of (+)-SKF-10,047 was superior to those of other sigma receptor ligands, and was mediated by both the sigma receptor and the central acetylcholinergic system.
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PMID:Ameliorating effects of sigma receptor ligands on the impairment of passive avoidance tasks in mice: involvement in the central acetylcholinergic system. 800 52

The effects of sigma ligands on the central acetylcholine (ACh) systems in the rat frontal cortex were examined. By using brain microdialysis techniques, we showed that nonbenzomorphan sigma ligands, (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine and 1,3-di(2-tolyl)guanidine (DTG) dose-dependently increased the extracellular ACh level in this area. Similarly, benzomorphan sigma ligands, (+/-)-pentazocine and (+)-N-allylnormetazocine [(+)-SKF-10,047] also increased the extracellular ACh level. The increase in extracellular ACh level elicited by (+)-SKF-10,047 was greater than that by (-)-SKF-10,047. Moreover, the (+)-SKF-10,047- and DTG-induced increase in the extracellular ACh level were reduced significantly by simultaneous administration of haloperidol, a putative sigma receptor antagonist, whereas the (+)-SKF-10,047-induced increase was unaffected by (+/-)-3-(2- carboxypiperazin-4-yl)-propyl-1-phosphonic acid, a competitive N-methyl-D-aspartate receptor channel antagonist. On the other hand, none of the sigma ligands tested in this study had any effects on acetylcholinesterase or choline acetyltransferase activity and sodium-dependent high affinity choline uptake site in the rat frontal cortex. Ranking of potency for increasing extracellular ACh level was in the following order: (+/-)-pentazocine > (+)-SKF-10,047 > (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine > DTG. This order was positively correlated with the order of binding potency for the (+)-[3H]SKF-10,047 binding site in the rat frontal cortex, but was not correlated with binding to the [3H]DTG, [3H]quinuclidinyl benzylate and [3H]AF-DX116 ([3H]11-[(2-[(dimethylamino)methyl]-1-piperidinyl)acetyl]-5, 11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one) binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Increase in extracellular acetylcholine level by sigma ligands in rat frontal cortex. 849 30

Three iodinated benzamides, 5-7, analogues of the potent acetylcholinesterase inhibitor 1-benzyl-4-[N-[4'-(benzylsulfonyl) benzoyl-N-methylamino]ethyl]piperidine (2), were synthesized and evaluated as potential anticholinesterase agents. All three compounds were found to be three orders of magnitude less potent than the parent compound. However, receptor screening revealed that compounds 5-7 exhibit nanomolar affinity for the sigma binding site. Both [125I]5 and [125I]7 were synthesized and evaluated in rats. Following the intravenous administration of [125I]5 into rats, 1.59% of the injected dose was found in the rat brain within 5 min. The level of radioactivity in the brain remained steady for 2 h, the duration of the study. In contrast, 0.42% of the injected dose was detected in the rat brain following the i.v. injection of [125I]7. Coadministration of either [125I]5 or [125I]7 with 0.5 mumol/kg of haloperidol resulted in a 56-73% reduction in the level of radioactivity in the rat brain, suggesting that these compounds bind to the sigma binding site in vivo. Planar imaging studies with [123I]5 revealed significant accumulation of radioactivity within the monkey brain, with a half-life of 6 h. Compound [123I]5 may be potentially useful for studying sigma receptor distribution in the human brain.
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PMID:Synthesis and biological evaluation of radioiodinated N-2-(4-piperidyl)ethyl benzamides. 850 92

We found that 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl) piperazine dihydrochloride (SA4503), a potent and selective sigma 1 receptor agonist, significantly enhanced the cerebral acetylcholine (ACh) release in the rat using in vivo brain microdialysis technique. Interestingly, the significant enhancement of ACh release elicited by SA4503 was observed in the rat frontal cortex and hippocampus, although the striatal ACh release was unchanged. This cortical ACh release was fully reversed by haloperidol, a prototype sigma receptor antagonist, or by N, N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride, a putative sigma 1 receptor antagonist. In addition, this enhanced ACh release by SA4503 was inhibited by tetrodotoxin, a Na+ channel blocker. However, tetrahydroaminoacridine, an acetylcholinesterase inhibitor, significantly increased the extracellular ACh level in the rat frontal cortex and weakly increased the hippocampal level. This compound also showed the significant increase of extracellular ACh level in the rat striatum. Moreover, tetrahydroaminoacridine markedly produced cholinomimetic side-effects, such as hypothermia, tremor, miosis and lacrimation. However, SA4503 did not produce these cholinomimetic side-effects. These findings suggest that SA4503 enhances the ACh release that is mediated through a novel mechanism, namely sigma 1 receptor subtype. Furthermore, SA4503 has regional differences in the enhancement of cerebral ACh release, and did not produce cholinomimetic side-effects. These profiles are different from tetrahydroaminoacridine.
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PMID:Enhancement of acetylcholine release by SA4503, a novel sigma 1 receptor agonist, in the rat brain. 885 82

We examined the ameliorating effects of several sigma receptor agonists on scopolamine-induced memory impairment in mice. Scopolamine was administered IP 30 min before the training session. Each sigma receptor agonist was administered 60 min before or immediately after the training session, or 60 min before the retention test in the passive-avoidance performance experiments. (+)-N-Allylnormetazocine ((+)-SKF-10,047), a prototype sigma 1 receptor agonist, showed an ameliorating effect on the scopolamine-induced memory impairment in these 3 administration schedules, and (-)-SKF-10,047, a stereoisomer with low affinity for the sigma 1 receptor subtype, failed to reduce this memory impairment in mice. In addition, 1,3-di(2-toly1)guanidine (DTG) and (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperizine ((+)-3-PPP), nonselective sigma receptor agonists, did not affect this memory impairment. Physostigmine, an acetylcholinesterase (AChE) inhibitor, alleviated the scopolamine-induced memory impairment in all these drug administration schedules. In addition, (+)-SKF-10,047-induced antiamnesic effect was antagonized by the concurrent administration of haloperidol, a sigma receptor antagonist, or N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy) phenyl)ethylamine monohydrochloride (NE-100), a selective sigma 1 receptor antagonist. These findings indicate that the sigma 1 receptor agonist has ameliorating effects on all phases of learning and memory processes. This profile of sigma 1 receptor agonist is similar to that of an AChE inhibitor.
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PMID:Reduction of the scopolamine-induced impairment of passive-avoidance performance by sigma receptor agonist in mice. 903 56

We found a potent and selective sigma 1 (sigma 1) receptor ligand, SA4503 (1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride). This compound had a high affinity for sigma 1 receptor subtype (IC50 = 17 +/- 1.9 nM), but a low affinity for sigma 2 receptor subtype (IC50 = 1800 +/- 310 nM). The present study examines the effect of this compound on the central cholinergic functions, since sigma receptor has been reported to interact with the central cholinergic neurons. SA4503 elicited the increase in extracellular acetylcholine level in rat frontal cortex, while it did not affect the striatal acetylcholine level. On the other hand, tetrahydroaminoacridine (THA), an acetylcholinesterase (AChE) inhibitor, increased the extracellular acetylcholine level in both regions. Although both compounds had anti-amnesic effect against scopolamine-induced memory impairment, THA also induced catalepsy in rats. These results suggest that SA4503 may be a novel cognitive enhancer, with sigma 1 receptor agonistic properties. In addition, SA4503 does not cause striatal cholinomimetic side-effects, which is different from THA.
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PMID:SA4503, a novel cognitive enhancer, with sigma 1 receptor agonistic properties. 906 89

Sigma and 5-HT(1A) receptor stimulation can increase acetylcholine (ACh) release in the brain. Because ACh release facilitates learning and memory, we evaluated the degree to which OPC-14523 (1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2[1H]-quinolinone monomethane sulfonate), a novel sigma and 5-HT(1A) receptor agonist, can augment ACh release and improve learning impairments in rats due to cholinergic- or age-related deficits. Single oral administration of OPC-14523 improved scopolamine-induced learning impairments in the passive-avoidance task and memory impairment in the Morris water maze. The chronic oral administration of OPC-14523 attenuated age-associated impairments of learning acquisition in the water maze and in the conditioned active-avoidance response test. OPC-14523 did not alter basal locomotion or inhibit acetylcholinesterase (AChE) activity at concentrations up to 100 microM and, unlike AChE inhibitors, did not cause peripheral cholinomimetic responses. ACh release in the dorsal hippocampus of freely moving rats increased after oral delivery of OPC-14523 and after local delivery of OPC-14523 into the hippocampus. The increases in hippocampal ACh release were blocked by the sigma receptor antagonist NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)-phenyl]-ethylamine). Thus, OPC-14523 improves scopolamine-induced and age-associated learning and memory impairments by enhancing ACh release, due to a stimulation of sigma and probably 5-HT(1A) receptors. Combined sigma/5-HT(1A) receptor agonism may be a novel approach to ameliorate cognitive disorders associated with age-associated cholinergic deficits.
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PMID:Attenuation of scopolamine-induced and age-associated memory impairments by the sigma and 5-hydroxytryptamine(1A) receptor agonist OPC-14523 (1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2[1H]-quinolinone monomethanesulfonate). 1190 81

5,7-Dihydro-3-[2-[1-(2-fluorobenzyl)-4-piperidinyl]ethyl]-6H-pyrrolo[3,2,f]-1,2-benzisoxazol-6-one (2-flouro-CP-118,954; 1), a potent acetylcholinesterase (AChE) inhibitor, was prepared as a radioligand by reductive alkylation of CP-144,885 the debenzylated form of CP 118,954, with 2-[18F]fluorobenzaldehyde. The decay-corrected radiochemical yield was 25-30% and the effective specific activity was 41-53 GBq/micromol. Tissue distribution studies of 2-[18F]fluoro-CP-118,954 ([18F]1) in mice showed that the regional brain distribution correlated well with the known density of AChE in the mouse brain. A high level of uptake in the striatum was also shown at all time points in the olfactory tubercle, which is known to have dopaminergic neurons. Blocking studies showed that radioligand uptake in all brain regions was not altered by either the dopamine receptor antagonists or the sigma receptor agonist. On the other hand, radioligand uptake in both the striatum and the olfactory tubercle was significantly blocked (80%) by ligand 1. The low level of bone uptake over time suggested that [18F]1 underwent little in vivo metabolic defluorination. The lack of metabolite formation in the mouse brain indicated that the regional distribution was attributed to [18F]1. These results demonstrated that [18F]1 binds specifically and selectively to AChE in mice and appears to be a suitable radioligand for the in vivo mapping of AChE.
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PMID:Synthesis and evaluation of 2-[18F]fluoro-CP-118,954 for the in vivo mapping of acetylcholinesterase. 1572 64

The main thrust of the meeting was, as always, basic research in behavioral neuroscience defined in a broad sense. Learning and memory, feeding and drinking, reward mechanisms, development of the CNS, anxiety and stress were the main topics covered. In a public lecture associated with the meeting, Larry Reid (Rensselaer Polytechnic Institute, Troy, NY, USA) reviewed the quite compelling evidence in favor of the effectiveness of naltrexone for preventing relapse in former alcoholics. He also presented preclinical data demonstrating the remarkable effects of naltrexone given together with isradipine (Novartis AG) in blocking the rewarding effects of cocaethylene. This combination of drugs could thereby constitute a treatment for alcoholism complicated by cocaine abuse. Of potential therapeutic interest was also the description of the preclinical pharmacology and a phase II trial of a new cholinesterase inhibitor, methanesulfonyl fluoride (University of Texas). The possible physiological functions of sigma opioid receptors and the pharmacological properties of sigma receptor ligands were discussed at one of the symposia. Among the subjects covered were the potential use of sigma1 antagonists in the treatment of cocaine addiction and the efficiency of sigma1 agonists for preventing the decline in cognitive functions associated with old age.
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PMID:International Behavioral Neuroscience Society - ninth annual meeting. 1608 41

Donepezil is a potent acetylcholinesterase inhibitor that also interacts with the sigma1 receptor, an intracellular neuromodulatory protein. In the present study, we analyzed the antiamnesic and neuroprotective activities of donepezil in a mouse hypoxia model induced by repetitive CO exposure, comparing donepezil's pharmacological profile with other cholinesterase inhibitors tacrine, rivastigmine, and galanthamine, and the reference sigma1 agonist igmesine. CO exposure induced, after 7 days, hippocampal neurodegeneration, analyzed by Cresyl violet staining, and behavioral alterations, measured using spontaneous alternation and passive avoidance responses. When injected 20 min before the behavioral tests, i.e., 7 to 8 days after CO, all drugs showed antiamnesic properties. Preadministration of the sigma1 receptor antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD1047) blocked only the igmesine and donepezil effects. The neuroprotective activity of the drugs was tested by injection 20 min before the first CO exposure (preinsult protection) or by injection 1 h after the last CO exposure (postinsult protection). All drugs alleviated the hypoxia-induced neurodegeneration and behavioral impairments when injected before CO exposure. Preadministration of BD1047 blocked both the igmesine and donepezil effects. However, when injected after CO exposure, only igmesine and donepezil induced effective neuroprotection, and the morphological and behavioral effects were BD1047-sensitive. These results showed that donepezil is a potent antiamnesic and neuroprotective compound against the neurodegeneration induced by excitotoxic insult, and its pharmacological actions as both an acetylcholinesterase inhibitor and sigma1 receptor agonist contribute to its marked efficacy. In particular, the drug is a more potent postinsult protecting agent compared with more selective cholinesterase inhibitors.
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PMID:Antiamnesic and neuroprotective effects of donepezil against learning impairments induced in mice by exposure to carbon monoxide gas. 1655 35


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