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:3.1.1.8 (cholinesterase)
12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MF-268 bitartrate [(3a S, 8a R)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol- 5-ol[8-(cis2,-6-dimethyl-morpholin-4-yl)octyl]-carbamate L-bitartrate hydrate; Mediolanum Farmaceutici, Milan, Italy] is a pseudo-reversible carbamate-type cholinesterase inhibitor (ChEI) which interacts with the catalytic and regulatory anionic site of the enzyme. Its effects on extracellular levels of acetylcholine (ACh), norepinephrine (NE), dopamine (DA), and serotonin (5-HT, 5-hydroxytryptamine) were studied in rat cortex by using a microdialysis technique coupled with high-performance liquid chromatography-electrochemical detection (HPLC-ECD). Conscious, freely moving rats were systemically [per os (p.o.) and subcutaneously (s.c.)] administered MF-268 with no ChEI in the probe. Cholinesterase inhibition in brain was assayed in parallel experiments. Oral administration of MF-268 (0.5, 2.0, and 5.0 mg/kg) produced a significant increase of extracellular ACh in cortex; the maximal increase was 300% [not significant (n.s.)], 460% and 1,200%, respectively. Maximal cholinesterase (ChE) inhibition was 2.3% (n.s.) at 9 hr and 9.7% (P < .05) at 12 hr after the 2.0 and 5.0 mg/kg doses, respectively. Norepinephrine and DA levels were increased 180% and 100% after the 5.0 mg/kg dose, respectively; 100% and 60% after the 2.0 mg/kg dose, respectively; and 70% for both amines after the 0.5 mg/kg dose, respectively. The elevation lasted at least 5 hr with the 2.0 and 5.0 mg/kg doses. There were no major changes in 5-HT levels at these three doses. Subcutaneous administration (0.5 and 2.0 mg/kg) produced a maximal 360% (5.5 hr) and 2,500% (5 hr) increase in extracellular ACh, respectively. Maximal ChE inhibition was 13% (0.5 mg/kg) and 41% (2.0 mg/kg). Neither 0.5 nor 2.0 mg/kg produced a consistent modification of NE. Only a transient increase in DA was seen with the 0.5 mg/kg dose. There were no changes in 5-HT levels at these two doses. MF-268-treated animals showed slight cholinergic side effects (chewing, tremor) at both doses. MF-268 administered intracortically through the microdialysis probe at a concentration of 50 microM induced a 5,900% increase in ACh levels at 6 hr. This effect started 30 min after injection and continued throughout the period of administration. MF-268 produced a significant decrease in NE levels (-44%) starting at 30 min, and a slight but significant increase in DA levels of 45% at 2.5 hr. A significant increase of 5-HT (58%) was also observed starting at 4 hr. Slight symptoms of cholinergic toxicity were observed during intracortical administration.
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PMID:Effects of MF-268, a new cholinesterase inhibitor, on acetylcholine and biogenic amines in rat cortex. 883 83

Recent years have seen the introduction of several new antidepressants, many of which have selective effects on serotonin (5-HT) pathways. In most patients these drugs are as effective as traditional tricyclic antidepressants and are somewhat better tolerated. In the most severe depressive disorders, however, drugs such as clomipramine, that produce potent inhibition of both 5-HT and noradrenaline reuptake may be more effective. Lithium is increasingly used in the treatment of resistant depression but its role in the short-term management of mania is less certain because of the increased risk of relapse on sudden discontinuation. In the treatment of mania and prophylaxis of bipolar disorder, carbamazepine and valproate are alternatives to lithium. In dementia, the cholinesterase inhibitor, tacrine, produces worthwhile improvement in about 40% of patients able to tolerate adequate doses. There is concern about adverse effects of antipsychotic drugs in patients with dementia, particularly those with Lewy body disease.
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PMID:Advances in psychopharmacology: mood disorders and dementia. 894 56

Anabaseine is a naturally occurring toxin that stimulates a variety of neuronal and muscle nicotinic receptors. GTS-21 [3-(2,4-dimethoxybenzylidene)anabaseine], an anabaseine derivative, selectively stimulates alpha 7-containing nicotinic receptors. Here we report the first in vivo study of the effects of these two nicotinic agonists on cortical extracellular acetylcholine (ACh), dopamine (DA), norepinephrine (NE) and serotonin (5-HT) levels, measured with a microdialysis probe placed within the frontoparietal cortex in the absence of a cholinesterase inhibitor. At 3.6 mumol/kg, s.c., anabaseine increased cortical ACh and NE above baseline values without significantly affecting DA and 5-HT. The ACh and NE elevations were inhibited by i.p. pre-administration (4.9 mumol/kg) of the nicotinic antagonist mecamylamine (Mec). In contrast, GTS-21 (3.6 mumol/kg, s.c.) significantly increased NE and DA without affecting ACh and 5-HT levels. Following Mec injection, GTS-21 increased ACh 25-fold and 5-HT 13-fold, while NE and DA levels were slightly decreased in comparison with GTS-21 alone. We suggest that at the dose used, Mec may preferentially block high affinity nicotinic receptors which normally provide an inhibitory influence upon ACh release, thereby permitting expression of the complete stimulatory effect of GTS-21 on neuronal alpha 7-receptors. GTS-21 and other receptor subtype-selective nicotinic agonists should be helpful in clarifying the roles of particular nicotinic receptors in modulating cortical neurotransmitter levels.
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PMID:Nicotinic agonist modulation of neurotransmitter levels in the rat frontoparietal cortex. 924 21

Several novel analogues of tacrine have been synthesized and tested for their ability to inhibit acetylcholinesterase, butyrylcholinesterase, and neuronal uptake of 5-HT (serotonin) and noradrenaline. Changes in the size of the carbocyclic ring of tacrine produced modest potency against cholinesterase enzymes. Addition of a fourth ring resulted in compounds with marked selectivity for acetylcholinesterase (AChE) over butyrylcholinesterase (BChE): e.g. 6-amino-4,5-benzo-5H-cyclopenta[1,2-b]-quinoline (14a) had an IC50 of 0.35 microM against AChE and 3.1 microM against BChE. Some tetracyclic compounds are 100-400 times more active than tacrine as inhibitors of neuronal uptake of serotonin, in particular 13-amino-6,7-dihydro-5H-benzo-[3,4]cyclohepta[1,2-b]quinoline (18), which had an IC50 of 20 nM. These compounds would be expected to facilitate both cholinergic and monoaminergic transmission. They should be worth investigating in models of memory impairment.
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PMID:Novel tacrine analogues for potential use against Alzheimer's disease: potent and selective acetylcholinesterase inhibitors and 5-HT uptake inhibitors. 935 18

The potency of a series of anticholinesterase (anti-ChE) agents and serotonin-related amines as inhibitors of the aryl acylamidase (AAA) activity associated with electric eel acetylcholinesterase (AChE) (EC 3.1.1.7) and horse serum butyrylcholinesterase (BuChE) (EC 3.1.1.8) was examined and compared with the potency of the same compounds as ChE inhibitors. Neostigmine, physostigmine, BW 284C51, (+/-)-huperzine A, E2020, tacrine, edrophonium and heptyl-physostigmine were, in that order, the most potent in inhibiting eel AChE-associated AAA activity, their inhibitor constant (Ki) values being in the range 0.02-0.37 microM. The rank order of the same compounds as AChE inhibitors basically paralleled that of AAA, although they were in general stronger on AChE (Ki = 0.001-0.05). The peripheral anionic site inhibitors propidium and gallamine were inactive on AChE-associated AAA. Serotonin and its derivatives were slightly stronger on AAA (Ki = 7.5-30 microM) than on AChE (Ki = 20-140 microM). Tacrine (IC50 = 0.03 microM), diisopropylfluorophosphate (IC50 = 0.04 microM), heptyl-physostigmine (IC50 = 0.11 microM), physostigmine (IC50 = 0.15 microM) and tetra-iso-propylpyrophosphoramide (iso-OMPA) (IC50 = 0.75 microM) were the most potent in inhibiting horse serum BuChE-associated AAA activity. Serotonin and related amines were very weak on BuChE-associated AAA activity. These results indicate that the inhibitory potencies of the active site anti-ChE agents on the AAA activity associated with eel AChE and horse serum BuChE are closely correlated with their action on the respective ChE. In addition, the efficacy of tacrine, E2020, heptyl-physostigmine and (+/-)-huperzine A in the treatment of Alzheimer's disease is unlikely to be related to the action of these drugs on ChE-associated AAA.
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PMID:Inhibition of cholinesterase-associated aryl acylamidase activity by anticholinesterase agents: focus on drugs potentially effective in Alzheimer's disease. 963 11

Recently synthesized triptans, sumatriptan derivatives, display aborting migraine activity at doses and with plasmatic maximum peak dramatically lower (20-40 times) than sumatriptan, the 5-HT like agonist, which is the original molecule. That triptans easily cross blood-brain barrier strongly supports the central theory of migraine. We recently discovered the anti-migraine prophylactic action of centrally acting anti-cholinesterase agents, that seems a further support to the central theory of migraine. Indeed, acetylcholine is an important analgesia neurotransmitter and is intertwined with 5-HT central pathways.
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PMID:Triptans. A support to the central link between serotonin and acetylcholine in migraine. 1072 Oct 55

Ascaris suum possesses a well-developed nervous system which is regulated by a number of classical neurotransmitters including acetylcholine (ACh), gamma-aminobutyric acid (GABA), glutamate and serotonin. The vagina vera, the distal part of the ovijector, displays intrinsic, rhythmic activity which has been shown to be modulated by FMRFamide-related peptides (FaRPs) in vitro. Confocal scanning laser microscopy coupled with immunocytochemistry, and histochemical studies, revealed that the nerve plexus of the ovijector contains GABAergic and glutamatergic innervation. Although no distinctive cholinergic or serotoninergic innervation was apparent, cholinesterase activity was localized to discrete areas of the musculature of the vagina vera. The effects of classical transmitters on the activity of the vagina vera in vitro were examined. ACh was excitatory, stimulating a brief but powerful contraction of the vagina vera with a threshold for activity of 1 microM. Both GABA and glutamate were inhibitory, causing a cessation of contractile activity at high concentrations (> 10 microM). Although less potent than glutamate, GABA had more profound effects and induced longer-lasting paralysis of the tissue. The threshold concentrations for activity were 5 microM for glutamate and 10 microM for GABA. Serotonin had no consistent effect on the vagina vera. This study demonstrates that classical transmitters modulate the activity of the ovijector of A. suum.
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PMID:Classical neurotransmitters in the ovijector of Ascaris suum: localization and modulation of muscle activity. 1108 52

The evidence for the involvement of cholinergic muscarinic receptors in mania and depression is reviewed. Small pilot trials with cholinesterase inhibitors and muscarinic agonists suggest that stimulation of muscarinic receptors may produce an antimanic effect, possibly by activation of muscarinic M(4) receptors. It is concluded that it is not likely that currently used mood stabilizers, such as lithium, valproic acid and carbamazepine, work directly through muscarinic receptor mechanisms. Furthermore, the evidence indicates that antipsychotic agents used for mania are working through the common mechanism of antagonism of dopamine D(2) receptors, and interactions with muscarinic receptors do not play a key role. Finally, it is hypothesized that olanzapine has robust antimanic activity, due to blockade of dopamine D(2) receptors and antagonism of other monoaminergic receptors. Olanzapine may normalize mood due to antidepressant-like activities, such as 5-HT(2A) receptor antagonism and increasing cortical norepinephrine and dopamine.
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PMID:Role of the cholinergic muscarinic system in bipolar disorder and related mechanism of action of antipsychotic agents. 1198 96

Acute colonic pseudo-obstruction (Ogilvie's syndrome) is characterized by an acute obstruction of the large bowel that is unrelated to mechanical causes. The evidence that cholinesterase inhibitors are effective in relieving acute colonic pseudo-obstruction raised interest in the pharmacological management of this condition. This review analyzes the pharmacological treatment of patients with Ogilvie's syndrome. Intravenous neostigmine is the best pharmacological treatment, leading to rapid colonic decompression. New colokinetic agents, including 5-HT(4) receptor agonists and motilides, may represent other useful therapeutic options for Ogilvie's syndrome.
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PMID:Prokinetics in the treatment of acute intestinal pseudo-obstruction. 1505 61

The present study examined, in mice, whether regional patterns of brain monoamines concentrations (DA, 5-HT and their metabolites) and expression of c-Fos protein, that may represent a prolonged functional change in neurons, could be changed after a combined exposure to stress and the peripheral cholinesterase reversible inhibitor pyridostigmine (PYR). Animals were subjected every day to a random combination of mild unescapable electric footshocks and immobilization over a 12-day period, resulting in a significant increase of glucocorticoids levels and an activation of c-fos in hippocampus, thalamus and piriform cortex. This stress protocol induced a significant increase of 5-HT levels in striatum, hippocampus and ponto mesencephalic area (PMA) but failed to induce any DA activation. When PYR (0.2 mg/kg s.c. inducing 19-35% inhibition of the plasmatic ChE activity) was administered twice a day during the last 5 days of the stress session, 5-HIAA levels and expression of c-fos oncogene were significantly increased in the most of the brain areas studied. DA levels were also enhanced in striatum/hippocampus as a result of a possible activation of mesolimbic and nigrostriatal dopamine systems. Taken together, these results suggest that a combined exposure to certain stress conditions and PYR leads, in mice, to functional changes in neurons and may affect centrally controlled functions. The mechanisms underlying these modifications and their behavioral implications remain to be further investigated.
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PMID:Peripheral ChE inhibition modulates brain monoamines levels and c-fos oncogene in mice subjected to a stress situation. 1601 84


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