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:3.4.16.2 (PCP)
3,761 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The nicotinic agonists dimethylphenylpiperazinium iodide (DMPP) and carbachol (CARB) as well as (-)nicotine [-)NIC) were tested alone and in combination with N-methyl-D-aspartate (NMDA) for their abilities to enhance the efflux of 3H-norepinephrine (NE) from slices of rat hippocampus. CARB and (-)NIC produced small, transient increases in NE efflux, while DMPP produced larger, longlasting increases. Inasmuch as the nicotinic antagonists mecamylamine (MECA) and hexamethonium (C6) did not consistently inhibit the increases in NE efflux produced by these agonists, the role of a nicotinic receptor in mediating these responses is uncertain. CARB and DMPP enhanced the ability of NMDA to stimulate NE release, while (-)NIC did not. MECA, but not C6, was found to selectively antagonize NMDA-stimulated NE release that did not appear to involve a nicotinic receptor. Binding studies indicated that MECA and the related nicotinic antagonist pempidine produced an inhibition of NMDA-stimulated NE release by an action at the PCP receptor that is known to be linked to the NMDA receptor-ionophore complex. These data suggest that the actions of these ganglionic blocking agents on excitatory responses in the hippocampus involve inhibition of excitatory amino acid as well as nicotinic receptors.
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PMID:Effects of nicotinic agonists and antagonists on N-methyl-D-aspartate-induced 3H-norepinephrine release and 3H-(1-[1-(2-thienyl)cyclohexyl]-piperidine) binding in rat hippocampus. 256 4

Recent studies from our laboratory have provided evidence that multiple states of the phencyclidine (PCP) receptor exist. In addition, several compounds such as PCP and the novel anticonvulsant MK-801 were found to inhibit binding more potently in the presence of Mg2+ and L-glutamate (L-GLU) than when these agents were excluded from the binding assay. In the present study, a number of pharmacological compounds that have been suggested to interact within the N-methyl-D-aspartate (NMDA) receptor complex, including tricyclic antidepressants (TCAs), were examined for their ability to inhibit the binding of [3H]1-[1-(2-thienyl)cyclohexyl]piperidine [( 3H]TCP) in the absence or presence of Mg2+ and L-GLU. The TCAs imipramine, amitriptyline, and opipramol produced shallow inhibition curves in the absence of Mg2+ and L-GLU. Computer analysis of the binding data indicated that a two-component binding model described the data significantly better than a one-component model. In the presence of Mg2+ and L-GLU, the inhibition curves became steeper and were shifted to the right, and computer analysis of the binding data indicated that a one-component model adequately described the binding data. A series of other centrally active compounds, including several antipsychotics and antihistamines, the antiparkinsonian anticholinergic trihexyphenidyl and the antitussive dextromethorphan, were also found to be affected similarly by the inclusion of Mg2+ and L-GLU in the binding assay. Dextrorphan, in contrast to dextromethorphan, inhibited [3H]TCP binding more potently in the presence of Mg2+ and L-GLU. The present results suggest that the compounds that inhibit binding more potently in the absence of Mg2+ and L-GLU are interacting with the PCP receptor in a different manner from that of PCP and MK-801, because these open-channel blockers inhibit [3H]TCP binding more potently in the presence of Mg2+ and L-GLU. The data support previous findings that TCAs interact with the NMDA receptor complex and suggest that the compounds trihexyphenidyl and dextromethorphan, which have been shown to block NMDA-mediated neurotoxicity, may produce their effects through an interaction with the PCP receptor, albeit by a different mechanism from that of open-channel blockers.
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PMID:Tricyclic antidepressants and dextromethorphan bind with higher affinity to the phencyclidine receptor in the absence of magnesium and L-glutamate. 256 80

These studies were conducted to determine whether amygdaloid kindling results in the long-term alteration of NMDA receptors which could explain the persistent reduction in seizure threshold seen in this phenomenon. NMDA-induced [3H]norepinephrine (NE) release, NMDA-sensitive L-[3H]glutamate binding, and NMDA and glycine-enhanced [3H]TCP binding were measured in brain tissue from kindled rats and nonstimulated control rats 3 to 6 weeks after the last seizure. There was no difference in the ability of NMDA to induce [3H]NE release from kindled or control slices of amygdala or hippocampus. There was also no difference in the ability of phencyclidine (PCP) or Mg2+ to inhibit [3H]NE release induced by 100 microM NMDA. Equilibrium saturation experiments of NMDA-sensitive L-[3H]glutamate binding revealed no differences in KD or Bmax values between control and kindled cortex, amygdala, and hippocampus. The Ki values for NMDA displacement of L-[3H]glutamate binding also did not differ in kindled tissue. NMDA-enhanced [3H]TCP binding was similar in cortex, amygdala, and hippocampus of kindled and control tissues. Finally, glycine-enhanced [3H]TCP binding was not different in control or kindled tissues. These studies suggest that the NMDA recognition site and the modulation of the NMDA receptor/ion channel complex by magnesium, PCP, and glycine are not altered several weeks after the last seizure. Even though NMDA-mediated electrophysiological responses are reportedly enhanced in kindled tissue at that time, the mechanism(s) underlying the enhancement remains to be determined.
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PMID:Effects of amygdaloid kindling on NMDA receptor function and regulation. 257 16

1-Phenylcyclohexylamine (PCA), an analog of phenyclidine (PCP) in which the piperidine ring is replaced by a primary amino group, and its conformationally restricted analog 1,1-pentamethylenetetrahydroisoquinoline (PM-THIQ) were potent anticonvulsants in the mouse maximal electroshock (MES) seizure test (ED50 values, 7.0 and 14.3 mg/kg, respectively). At higher doses, the drugs caused motor impairment (TD50 values, 16.3 and 43.0 mg/kg) and blocked the behavioral effects and lethality of i.p. injected N-methyl-D-aspartate (NMDA) (ED50 values, 36.3 and 127 mg/kg). The separation in potencies in the MES seizure and motor toxicity tests of PCA and PM-THIQ contrasts with PCP which was equally potent in both tests. Several compounds that were structurally related to PM-THIQ (N-ethyl-PCA, 2-methyl-PCA, N-methyl-PM-THIQ, tetrahydroisoquinoline and benzylamine) also blocked MES seizures and caused motor impairment, but failed to show as great a separation between MES anticonvulsant activity and motor toxicity. None of the compounds protected against seizures induced by the chemoconvulsant pentylenetetrazol at doses that lacked motor toxicity. The drugs were also evaluated for their ability to displace [3H]-1-[1-(2-thienyl)-cyclohexyl]piperidine from binding to high affinity acceptor sites (presumably on NMDA receptor-coupled channels) in rat brain homogenates. The rank order of potencies in the binding assay was similar to that in the behavioral tests, except for 2-methyl-PCA which was behaviorally more potent than expected.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Anticonvulsant activities of 1-phenylcyclohexylamine and its conformationally restricted analog 1,1-pentamethylenetetrahydroisoquinoline. 265 75

Ketamine and (+)-N-allylnormetazocine ((+)-NANM) were found to generalize in a rat operant drug discrimination paradigm to the interoceptive stimulus induced by phencyclidine (PCP). Intraperitoneal administration of the non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, MK-801, and intracerebroventricular injection of the competitive antagonist, 2-DL-amino-7-phosphonoheptanoic acid (2-APH), also resulted in a dose-dependent generalisation to the PCP discriminative stimulus. The results suggest that NMDA receptor antagonism may play an important role in the mediation of the discriminative stimulus properties of PCP. The low potency of MK-801 and 2-APH to displace [3H](+)-NANM binding in vitro argues against an involvement of the haloperidol-sensitive sigma recognition site in the behaviour.
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PMID:A role for receptors of N-methyl-D-aspartic acid in the discriminative stimulus properties of phencyclidine. 282 52

The nature of the interactions between the N-methyl-D-aspartate (NMDA) and the phencyclidine (PCP) receptors was studied in membranes obtained from rat cerebral cortex and washed repeatedly to remove endogenous excitatory amino acids. Binding of [3H]-N-[1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP) to its receptor sites in these membranes proceeded slowly and did not reach equilibrium even after incubation for 4 h at 25 degrees C. The dissociation rate of [3H]TCP-receptor complexes was also slow (t1/2 = 128-165 min). Both association and dissociation followed first-order reaction kinetics, with similar time constants (0.0054 min-1). Addition of glutamate and glycine to the washed membranes was immediately followed by a marked increase in the rates of both association of [3H]TCP with the receptors and its dissociation from them (t1/2 = 8 min). Association now followed second-order reaction kinetics. Accelerated association of [3H]TCP with its binding sites could also be induced by NMDA or by glutamate alone, and glycine enhanced the effect. All effects of glutamate and glycine on [3H]TCP binding kinetics were blocked by the competitive NMDA receptor antagonist AP-5 [D-(-)-2-amino-5-phosphovaleric acid]. [3H]TCP-receptor interactions at equilibrium were not altered by AP-5 or by glutamate and glycine. The binding data were fitted to a model in which interactions of [3H]TCP with the receptor involve a two-step process: the outside ligand must cross a barrier (presumably a closed NMDA receptor channel in the absence of agonists). Once agonists are added, this limitation is removed (presumably because the channel is open).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Kinetic characterization of the phencyclidine-N-methyl-D-aspartate receptor interaction: evidence for a steric blockade of the channel. 283 78

N-Methyl-D-aspartate (NMDA), phencyclidine (PCP), and quisqualate receptor binding were compared to benzodiazepine, gamma-aminobutyric acid (GABA), and muscarinic cholinergic receptor binding in the putamen and cerebral cortex of individuals with Huntington's disease (HD). NMDA receptor binding was reduced by 93 percent in putamen from HD brains compared to binding in normal brains. Quisqualate and PCP receptor binding were reduced by 67 percent, and the binding to other receptors was reduced by 55 percent or less. Binding to these receptors in the cerebral cortex was unchanged in HD brains. The results support the hypothesis that NMDA receptor-mediated neurotoxicity plays a role in the pathophysiology of Huntington's disease.
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PMID:NMDA receptor losses in putamen from patients with Huntington's disease. 284 62

Transient brain ischemia results in a selective destruction of cell bodies within the hippocampus and cortex. This cellular destruction appears to be mediated through a release of endogenous exictatory amino acids following the ischemic episode, since the neurotoxic effects of ischemia can be attenuated by compounds that have antagonist activity at N-methyl-D-aspartate (NMDA) receptors. In the present study, the protective effects of a novel NMDA receptor antagonist, CGS 19755, were further evaluated by using quantitative autoradiography to characterize adenosine A1, NMDA, PCP, and benzodiazepine receptors in ischemic gerbil brain. Bilateral carotid artery occlusion (20 minutes) resulted in marked decreases (30-60%) in adenosine A1, NMDA, and PCP, but not benzodiazepine, receptors in gerbil forebrain. Postischemic treatment with CGS 19755 was found to completely block the ischemia-induced decreases in brain adenosine and NMDA receptors. [3H]TCP binding in ischemic gerbil brain was also elevated by CGS 19755 treatment; significant differences remained, however, between the CGS 19755-treated and control gerbils. These results indicate that transient brain ischemia produces significant and selective alterations in gerbil forebrain receptor systems. The observed decreases in radioligand binding are probably reflective of an ischemia-induced destruction of forebrain structures. However, there is some evidence that transient ischemia can also cause long-term changes in the affinity of some receptor systems. The postischemic efficacy of CGS 19755 appears to be due to its ability to block the neurotoxic effects of transient ischemia.
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PMID:The novel N-methyl-D-aspartate (NMDA) antagonist CGS 19755 prevents ischemia-induced reductions of adenosine A1, NMDA, and PCP receptors in gerbil brain. 285 Jun 32

The neurotransmitter glutamate activates the N-methyl-D-aspartate (NMDA), quisqualate and kainate receptors. It has been proposed, but also disputed, that local release of glutamate would play a pivotal role in cortical spreading depression (SD). We tested this hypothesis by investigating the influence of NMDA antagonists on SD, using the non-competitive NMDA antagonists ketamine, phencyclidine (PCP) and MK-801 and the competitive NMDA antagonist DL-2-amino-7-phosphonoheptanoate (2-APH), injected intraperitoneally in rats anesthetized with alfentanil. SD was elicited by cathodal DC-stimulation of the frontal cortex. SD propagation was followed using two ion-sensitive microelectrodes placed in the parietal and occipital cortex. The NMDA antagonists increased SD threshold, decreased the propagation velocity and decreased the duration of the accompanying extracellular DC, K+ and Ca2+ changes at the following doses: 40 mg/kg ketamine, 10 mg/kg PCP, 0.63 mg/kg MK-801, 10 and 40 mg/kg 2-APH. With each NMDA antagonist failure of SD propagation between both microelectrodes could be observed. SD elicitation (or propagation) was inhibited completely with 80 mg/kg ketamine, 3.1 mg/kg MK-801 and 160 mg/kg 2-APH. These NMDA antagonists have also anticonvulsant properties. None of these effects on SD were observed with high doses of other anticonvulsants such as 80 mg/kg phenytoin or 40 mg/kg diazepam. These experiments indicate that endogenous release of excitatory amino acids and their action on the NMDA receptor play an important role in the initiation, propagation and duration of SD.
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PMID:Evidence for a role of the N-methyl-D-aspartate (NMDA) receptor in cortical spreading depression in the rat. 285 64

D-(-)-2-Amino-5-phosphonovaleric acid (D(-)AP5), a selective, potent competitive antagonist of N-methyl-D-aspartate (NMDA)-type excitatory amino acid receptors was used to investigate the relationship between NMDA receptors and phencyclidine (PCP) binding. Incubation of rat brain membranes with D(-)AP5 decreased the apparent number of PCP/sigma-receptors in dose-dependent fashion without affecting their affinity for [2-thienyl-3H]cyclohexylpiperidine (TCP). These data, taken together with electrophysiological evidence that PCP non-competitively antagonizes NMDA receptor-mediated transmission, are consistent with the hypothesis that the PCP/sigma-receptor may be situated in or near a channel regulated by an NMDA receptor complex.
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PMID:Non-competitive regulation of phencyclidine/sigma-receptors by the N-methyl-D-aspartate receptor antagonist D-(-)-2-amino-5-phosphonovaleric acid. 288 59


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