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)

The present experiments were performed to investigate the potential role of central adrenergic neurons in regulating occurrence of yawning in rats. Intraperitoneal injection of tacrine (THA) or 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta(b)-quinoline monohydrate HCl (NIK-247), cholinesterase inhibitors, induced yawning, which was markedly increased by pretreatment with the beta-adrenoceptor antagonist, pindolol. The yawning evoked by tacrine or NIK-247 given alone or in combination with pindolol was inhibited by pretreatment with scopolamine but not by mecamylamine or spiperone. Treatment with tacrine or NIK-247 increased acetylcholine content of the striatum, but this effect was not enhanced by pindolol, which per se did not affect basal acetylcholine content. Moreover, pretreatment with the central adrenaline synthesis inhibitors, (+-)-2,3-dichloro-alpha-methylbenzylamine HCl (LY-78335) and 2-cyclooctyl-2-hydroxyethylamine HCl (UK-1187A), increased tacrine-induced yawning. Subcutaneous injection of talipexole (B-HT 920), a dopamine D2 receptor agonist, evoked yawning, which was also increased by pindolol, LY-78335, and UK-1187A. These receptors antagonists and synthesis inhibitors per se did not cause yawning responses. The results suggest that the beta-adrenoceptor blockade and the inhibition of adrenaline synthesis facilitate the occurrence of yawning induced by cholinergic and dopaminergic agonists, and thus the central adrenergic neuronal systems may be implicated in the regulation of yawning responses.
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PMID:Role of adrenergic neuronal activity in the yawning induced by tacrine and NIK-247 in rats. 136 95

Structure-function relationships of cholinesterases (CHEs) were studied by expressing site-directed and naturally occurring mutants of human butyrylcholinesterase (BCHE) in microinjected Xenopus oocytes. Site-directed mutagenesis of the conserved electronegative Glu441,Ile442,Glu443 domain to Gly441,Ile442,Gln443 drastically reduced the rate of butyrylthiocholine (BTCh) hydrolysis and caused pronounced resistance to dibucaine binding. These findings implicate the charged Glu441,Ile442,Glu443 domain as necessary for a functional CHE catalytic triad as well as for binding quinoline derivatives. Asp70 to Gly substitution characteristic of 'atypical' BCHE, failed to alter its Km towards BTCh or dibucaine binding but reduced hydrolytic activity to 25% of control. Normal hydrolytic activity was restored to Gly70 BCHE by additional His114 or Tyr561 mutations, both of which co-appear with Gly70 in natural BCHE variants, which implies a likely selection advantage for these double BCHE mutants over the single Gly70 BCHE variant. Gly70 BCHE variants also displayed lower binding as compared with Asp70 BCHE to cholinergic drugs, certain choline esters and solanidine. These effects were ameliorated in part by additional mutations or in binding solanidine complexed with sugar residues. These observations indicate that structural interactions exist between N' and C' terminal domains in CHEs which contribute to substrate and inhibitor binding and suggest a crucial involvement of both electrostatic and hydrophobic domains in the build-up of the CHE active center.
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PMID:Intramolecular relationships in cholinesterases revealed by oocyte expression of site-directed and natural variants of human BCHE. 137 81

Basal and high K(+)-stimulated efflux of endogenous ACh from slices of brain was measured to evaluate the cholinomimetic effect of 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b] quinoline monohydrate HCl (NIK-247) on the central nervous system. The drug NIK-247 dose-dependently accelerated the efflux of ACh from slices of striatum. The maximum increase produced by 1.0 x 10(-4) M of NIK-247 was 329% in basal and 1332% in 30 mM K(+)-stimulated efflux. This drug was nearly twice as potent as THA (9-amino-1,2,3,4-tetrahydroacridine HCl) but had the same potency as physostigmine, in enhancing basal efflux, although there was no significant difference between the efficacy of these drugs in enhancing the K(+)-stimulated efflux. Both basal and 50 mM K(+)-stimulated efflux of ACh were increased by NIK-247, not only from the striatum but also from slices of frontal cortex and hippocampus. The activity was more effective in the striatum than in other tissues, and more effective on K(+)-stimulated than on basal efflux, regardless of the region of the brain. These effects of NIK-247 may be a result mainly of its inhibition of cholinesterase and its other biological characteristics, such as K+ channel blockade, capable of modulating release of ACh, may not be of major importance.
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PMID:Evaluation of a cholinomimetic drug, 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta [b] quinoline (NIK-247), as an enhancer of endogenous efflux of acetylcholine from brain slices. 154 4

In experiments on the isolated extensor digitorum longus muscle of the rat it was shown that 4-aminoquinoline (125-250 micro M) altered the amplitude distribution of spontaneous miniature endplate potentials to include a large portion of giant miniature endplate potentials with slow rise and decay times. Similar, slow-rising giant miniature endplate potentials were induced by the drug at neuromuscular junctions with regenerating nerve terminals, i.e. in a condition where spontaneous as well as evoked transmitter release is depressed. The appearance of giant miniature endplate potentials was not correlated with inhibition of cholinesterase since neostigmine (3 micro M) failed to induce such potentials. Nerve impulse evoked endplate potentials of amplitudes similar to the spontaneous giant miniature endplate potentials had a faster and more uniform rise time. The results suggest that 4-amino-quinoline, by a direct action on the nerve terminal, causes the release of larger than normal quanta of acetylcholine. Quantitative assays of acetylcholine released before and in the presence of 4-aminoquinoline gave similar values showing that the amounts of acetylcholine which give rise to the giant miniature potentials contribute little to the total amount of acetylcholine liberated.
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PMID:Giant miniature endplate potentials induced by 4-aminoquinoline. 713 13

"In vitro" studies have demonstrated that methyl-p-toluene sulfonates of 1-methyl-(ethyl)-3-aryl-benzo(f)quinolinium are highly efficient inhibitors of cholinesterases, the inhibition constants (Ki) for acetylcholinesterase and butyrylcholinesterase being equal to 2.20 +/- 0.49 and 9.43 +/- 0.39 mkM, respectively. The effect of these inhibitors on the enzyme is of competitive - non-competitive type. A certain role in benzo(f)quinoline binding to acetylcholinesterase apparently belongs to the interaction of substituents in the phenyl nucleus with the anionic sites located outside the active surface of the enzyme.
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PMID:[Anticholinesterase properties of benzo(f)quinolinium derivatives]. 730 95

We studied the effect of orally administered NIK-247 (9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinoline monohydrochloride monohydrate) on basal extracellular acetylcholine (ACh) concentrations in the rat cerebral cortex using microdialysis without the addition of cholinesterase inhibitor to the perfusion fluid and radioimmunoassay for ACh. In addition, the effect of oral administration of NIK-247 on acetylcholinesterase (AChE) activity in rat cerebral cortex was determined. The mean basal ACh content in the perfusate from the cerebral cortex of freely moving rats was 123.2 +/- 21.8 fmol/30 min (n = 7). NIK-247 (2.5-10.0 mg/kg, p.o.) increased the ACh content of the perfusate in a dose-dependent manner. NIK-247 at 10 mg/kg significantly increased the ACh content in the perfusate from 0.5 to 2.5 hr after administration, and the maximum increase was attained at 1 hr after administration. 9-Amino-1,2,3,4-tetrahydroacridine (5 mg/kg, p.o.) and physostigmine (0.5 mg/kg, i.p.) significantly increased the ACh content in the perfusate from 1 to 2 hr and from 0.5 to 1.5 hr after administration, respectively. AChE activities in the cerebral cortex were about 32% and 12% below the control value at 1 hr and 3 hr after administration of NIK-247 at 10 mg/kg, respectively. These findings demonstrate that NIK-247 increases extracellular ACh concentration and inhibits AChE activity in the cerebral cortex after oral administration, and they suggest that NIK-247 facilitates central cholinergic transmission.
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PMID:Effect of NIK-247 on basal concentrations of extracellular acetylcholine in the cerebral cortex of conscious, freely moving rats. 786 15

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

We investigated the effects of intracerebroventricular administration of NIK-247 (9-amino-2,3,5,6,7,8-hexahydro-1H-cyclo-penta(b)-quinoline monohydrate hydrochloride; a cholinesterase inhibitor) or MKC-231 (2-(2-oxypyrrolidin-1-yl)-N-(2,3-dimethyl-5,6,7,8-tetrahydrofur o[2,3-b]quinolin-4-yl) acetoamide; a choline uptake enhancer) on plasma glucose level in comparison with that of neostigmine administration in rats. The extents of NIK-247- and MKC-231-induced hyperglycemia were considerably less than that by neostigmine, suggesting that the potencies of the drugs to produce the peripheral hyperglycemia may be pharmacologically negligible.
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PMID:Central nervous system-mediated hyperglycemic effects of NIK-247, a cholinesterase inhibitor, and MKC-231, a choline uptake enhancer, in rats. 1008 25

Eleven new 12-amino-6,7,10,11-tetrahydro-7, 11-methanocycloocta[b]quinoline derivatives [tacrine (THA)-huperzine A hybrids, rac-21-31] have been synthesized as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. For derivatives unsubstituted at the benzene ring, the highest activity was obtained for the 9-ethyl derivative rac-20, previously prepared by our group. More bulky substituents at position 9 led to less active compounds, although some of them [9-isopropyl (rac-22), 9-allyl (rac-23), and 9-phenyl (rac-26)] show activities similar to that of THA. Substitution at position 1 or 3 with methyl or fluorine atoms always led to more active compounds. Among them, the highest activity was observed for the 3-fluoro-9-methyl derivative rac-28 [about 15-fold more active than THA and about 9-fold more active than (-)-huperzine A]. The activity of some THA-huperzine A hybrids (rac-19, rac-20, rac-28, and rac-30), which were separated into their enantiomers by chiral medium-pressure liquid chromatography (chiral MPLC), using microcrystalline cellulose triacetate as the chiral stationary phase, showed the eutomer to be always the levorotatory enantiomer, their activity being roughly double that of the corresponding racemic mixture, the distomer being much less active. Also, the activity of some of these compounds inhibiting butyrylcholinesterase (BChE) was tested. Most of them [rac-27-31, (-)-28, and (-)-30], which are more active than (-)-huperzine A as AChE inhibitors, turned out to be quite selective for AChE, although not so selective as (-)-huperzine A. Most of the tested compounds 19-31 proved to be much more active than THA in reversing the neuromuscular blockade induced by d-tubocurarine. Molecular modeling of the interaction of these compounds with AChE from Torpedo californica showed them to interact as truly THA-huperzine A hybrids: the 4-aminoquinoline subunit of (-)-19 occupies the same position of the corresponding subunit in THA, while its bicyclo[3.3.1]nonadiene substructure roughly occupies the same position of the corresponding substructure in (-)-huperzine A, in agreement with the absolute configurations of (-)-19 and (-)-huperzine A.
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PMID:Synthesis, in vitro pharmacology, and molecular modeling of very potent tacrine-huperzine A hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of Alzheimer's disease. 1046 10

Several new 12-amino-6,7,10,11-tetrahydro-7, 11-methanocycloocta[b]quinoline derivatives (tacrine-huperzine A hybrids, huprines) have been synthesized and tested as acetylcholinesterase (AChE) inhibitors. All of the new compounds contain either a methyl or ethyl group at position 9 and one or two (chloro, fluoro, or methyl) substituents at positions 1, 2, or 3. Among the monosubstituted derivatives, the more active are those substituted at position 3, their activity following the order 3-chloro > 3-fluoro > 3-methyl > 3-hydrogen. For the 1,3-difluoro and 1,3-dimethyl derivatives, the effect of the substituents is roughly additive. No significant differences were observed for the inhibitory activity of 9-methyl vs 9-ethyl derivatives mono- or disubstituted at positions 1 and/or 3. The levorotatory enantiomers of these hybrid compounds are much more active (eutomers) than the dextrorotatory forms (distomers) as AChE inhibitors. Compounds rac-20, (-)-20, rac-26, (-)-26, rac-30, (-)-30, and rac-31 showed human AChE inhibitory activities up to 28.5-fold higher than for the corresponding bovine enzyme. Also, rac-19, (-)-20, (-)-30, and rac-31 were very selective for human AChE vs butyrylcholinesterase (BChE), the AChE inhibitory activities being 438-871-fold higher than for BChE. Several hybrid compounds, specially (-)-20 and (-)-30, exhibited tight-binding character, showing higher activity after incubation of the enzyme with the inhibitor than without incubation, though the reversible nature of the enzyme-inhibitor interaction was demonstrated by dialysis. The results of the ex vivo experiments also supported the tight-binding character of compounds (-)-20 and (-)-30 and showed their ability to cross the blood-brain barrier. Molecular modeling simulations of the AChE-inhibitor complex provided a basis to explain the differences in inhibitory activity of these compounds.
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PMID:New tacrine-huperzine A hybrids (huprines): highly potent tight-binding acetylcholinesterase inhibitors of interest for the treatment of Alzheimer's disease. 1110 57


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