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 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

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

NIK-247 (9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]-quinoline hydrochloride hydrate), an acetylcholinesterase inhibitor, is structurally related to 4-aminopyridine (AP). Its effects on ionic currents were examined in the artificial node of the crayfish axon under voltage-clamp. When applied externally, NIK-247 reversibly suppressed both inward and outward currents. Effects on K currents were further studied in the presence of tetrodotoxin. NIK-247 suppressed the K current dose-dependently, but with an IC50 at of 10(-3) M. THA (9-amino-1,2,3,4-tetra-hydroacridine hydrochloride hydrate), a related inhibitor, similarly suppressed the K current with an IC50 of 5 x 10(-4) M, in comparison with 3-AP and 4-AP which had IC50's of 3 x 10(-5) M and at 10(-5) M, respectively. Furthermore, NIK-247 (and THA) suppressed the K current uniformly for the whole time course, whereas AP the AP's suppressed mainly the fast activating and inactivating K current with a voltage- and frequency-dependent recovery. Therefore, NIK-247 and THA seem to be neither potent nor very specific as ionic channel blockers. With respect to the K current, however, they clearly differ from the AP's in their mode of suppression.
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PMID:NIK-247 blocks voltage-dependent ionic currents in crayfish axon. 172 92

An in vitro comparison demonstrated that the concentration of NIK-247 that inhibited cholinesterase (ChE) activities to half the normal level (ID50) was 1.3 x 10(-6) M. This value was higher than those for both physostigmine (PHY; 1.2 x 10(-7) M) and tetrahydroaminoacridine (THA; 3.6 x 10(-7) M), which are used as cholinesterase inhibitors in the treatment of cholinergic deficits. Neither NIK-247 nor THA affected the activity of choline acetyltransferase (ChAT). These inhibitions of ChE by NIK-247 and PHY lasted for 2 h, while that by THA lasted for over 4 h. In the effects of NIK-247 and PHY, the concentrations of intrastriatal acetylcholine (ACh) were changed in relation to the inhibition of the ChE activity. However, THA caused a transient increase in the ACh level lasting for only 2 h instead of inhibiting the enzyme activity for over 4 h. These findings suggest that NIK-247 is a drug with a similar profile in its effect on cholinergic neurons to PHY, the prototype drug among ChE inhibitors. The data indicate that NIK-247 may be useful as a drug for the treatment of central as well as peripheral deficits of the cholinergic mechanism.
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PMID:Effect of 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta-(b)-quinoline monohydrate hydrochloride (NIK-247) on cholinergic enzyme activity in rats. 194 90

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

The effects of olfactory bulbectomy on the learning and memory of rats were examined, using several memory tasks. In reference memory and working memory tasks using a 3-panel runway apparatus, acquisition was delayed markedly by bilateral ablation of the olfactory bulb (OB). OB lesion performed after acquisition markedly impaired both reference and working memories. Even when the tasks were repeated for several sessions, the impairment of memory in OB-lesioned rats did not recover to the control level of the sham operation group. The delayed matching-to-lever location (DMLL) performance, which was examined using a 3-lever operant apparatus, was markedly impaired by OB lesions. This impairment was mild immediately after surgery, but tended to increase with time. Rats with OB-olfactory tubercule lesions show more severe impairment of memory in the DMLL performance. Reversal learning, using a 2-lever operant apparatus, was markedly impaired by OB lesions. The impairment of working and reference memories in OB lesioned rats, which was assessed using a 3-panel-runway apparatus, was reduced by cholinesterase inhibitor physostigmine and NIK-247. These findings suggest that the OB plays a very important role in the learning and memory processes necessary for both a working memory task and a reference memory task and that, at least in part, the memory impairment in OB lesioned rats is mediated by lowering of cholinergic function.
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PMID:Olfactory bulbectomy leads to learning/memory impairments in 3-panel runway and 3-lever operant tasks. 797 32

Using a three-panel runway task, the effects of NIK-247 on impairment of working memory produced by scopolamine, hippocampal lesions, and cerebral ischemia were investigated in rats; these effects were compared with those of the well-known cholinesterase inhibitors, tetrahydroaminoacridine (THA) and physostigmine. Intraperitoneal injection of scopolamine (0.56 mg/kg) significantly increased the number of errors (pushes made on the two incorrect panels of the three-panel gates located at four choice points). NIK-247 (3.2-18 mg/kg PO), THA (1-10 mg/kg PO), and physostigmine (0.1 and 0.32 mg/kg IP) dose-dependently reduced the increase in errors induced by scopolamine. NIK-247 (32 mg/kg) was also effective in reducing the increase in errors produced by lesions of the dorsal hippocampus. A 5-min period of cerebral ischemia markedly increased the number of errors. NIK-247 (3.2 and 10 mg/kg), given immediately after blood flow recirculation and again 20 min before the runway test carried out 24 h after ischemia, significantly reduced the increase in errors expected to occur after ischemia. Tetrahydroaminoacridine (3.2 mg/kg) and physostigmine (0.1 mg/kg) similarly reversed the increased errors in ischemic rats. These results suggest that NIK-247 alleviates the impairment of working memory produced by scopolamine, hippocampal lesions, and cerebral ischemia, possibly through activation of the central cholinergic system.
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PMID:Ameliorative effects of the centrally active cholinesterase inhibitor, NIK-247, on impairment of working memory in rats. 843 69

The discriminative stimulus effect of the novel centrally active cholinesterase inhibitor, NIK-247, was investigated in rats and compared with that of tetrahydroaminoacridine (THA). Rats were trained to discriminate either 10 mg/kg NIK-247 or 1.8 mg/kg THA from saline in a two-lever food-reinforced procedure. The stimulus effect of NIK-247 was substituted for by the cholinesterase inhibitors, THA and physostigmine. The THA stimulus was substituted for by NIK-247 and physostigmine. The muscarinic receptor agonist arecoline substituted for the NIK-247 and THA stimuli. Both stimulus effects of NIK-247 and THA were blocked by the muscarinic antagonist scopolamine. The dopaminergic-activating drugs amantadine and lisuride substituted for the stimulus effects of NIK-247 and THA. However, neither the NIK-247 nor the THA stimulus was antagonized by the dopamine antagonists haloperidol, SCH 23390, and sulpiride. These results suggest that the discriminative stimulus effects of NIK-247 and THA are mediated by muscarinic receptors, and that the dopaminergic activity resulting from cholinergic activation may account for some part of both stimuli.
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PMID:Discriminative stimulus properties of NIK-247 and tetrahydroaminoacridine, centrally active cholinesterase inhibitors, in rats. 846 88

The memory impairment of olfactory bulbs (OB)-lesioned rats was characterized using 4 different tasks of learning/memory, and the effects of certain cholinergic drugs on such memory impairment were examined. In reference memory and working memory tasks using a 3-panel runway apparatus, OB-lesioned rats showed a marked increase in errors. In the 3-lever operant task using delayed matching to a sample (DMTS) procedure, OB lesions significantly decreased the correct response in choice (test) trials without affecting the in sample (training) trials. An interesting finding is that impairment in the DMTS performance did not appear immediately after the OB lesion, but tended to appear after a delay. Based on this finding, it is unlikely that memory impairment in the OB-lesioned rats is due to the olfactory deficit itself. However, OB lesions significantly reduced the choice accuracy and delayed the choice reaction time during the 3-choice serial time task for assessing attentional function, using a 3-lever operant apparatus. These findings suggest that marked impairment of learning and memory in OB-lesioned rats may be caused by the attention deficit. Furthermore, the memory impairment in OB-lesioned rats was reduced by cholinesterase inhibitors, physostigmine and NIK-247. These finding suggest that dysfunction of the cholinergic system is involved, at least in part, in the memory impairment of OB-lesioned rats.
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PMID:Characteristics of memory dysfunction in olfactory bulbectomized rats and the effects of cholinergic drugs. 906 61

The effects of NIK-247 on cholinesterase, scopolamine-induced amnesia and spontaneous movement were examined and compared with those of the well-known cholinesterase inhibitors tacrine and E-2020. NIK-247, tacrine and E-2020 all strongly inhibited acetylcholinesterase (AChE) in human red blood cells (IC50s = 1.0 x 10(-6), 2.9 x 10(-7) and 3.7 x 10(-8) M, respectively). In addition, NIK-247 and tacrine, but not E-2020, strongly inhibited butyrylcholinestrase (BuChE) in human serum. All three drugs produced mixed inhibition of AChE activity. Moreover, the inhibitory effect of NIK-247 on AChE was reversible. All compounds at 0.1-1 mg/kg p.o. significantly improved the amnesia induced by scopolamine (0.5 mg/kg s.c.) in rats performing a passive avoidance task. The three compounds at 1 and 3 mg/kg p.o. did not significantly decrease spontaneous movement by rats. These findings suggest that NIK-247 at a low dose (0.1-1 mg/kg p.o.) improves scopolamine-induced amnesia but does not affect spontaneous movement. The findings suggest that NIK-247 may be a useful drug for the treatment of Alzheimer's disease.
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PMID:Effects of NIK-247 on cholinesterase and scopolamine-induced amnesia. 922 50


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