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 effect of systemically administered phencyclidine (PCP) on the extracellular concentration of aspartate (Asp) and glutamate (Glu) in the rat anterior cingulate cortex was investigated using in vivo microdialysis. PCP significantly reduced the K(+)-evoked release of Asp and Glu, while it had no effect on the basal efflux of Asp and Glu. These results suggest that PCP might inhibit excitatory amino acid (EAA) release through an N-methyl-D-aspartate (NMDA) receptor-mediated mechanism.
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PMID:Effect of phencyclidine on endogenous excitatory amino acid release from the rat anterior cingulate cortex--an in vivo microdialysis study. 790 19

The phencyclidine (PCP) receptor is located within the N-methyl-D-aspartate (NMDA) receptor-gated ion channel. The functional state of the NMDA receptor complex thus influences parameters of radioligand binding to the PCP receptor, and PCP receptor ligands can serve as in vitro probes for elucidation of NMDA receptor activation mechanisms. PCP receptor binding is stimulated by NMDA receptor agonists such as L-glutamate and also by distinct classes of modulatory agents such as glycine-like amino acids and polyamines such as spermidine (SPD). The present study utilizes a kinetic approach permitting differentiation of PCP receptor binding within closed and activated conformations of the NMDA receptor complex. The results demonstrate that SPD increases radioligand binding to the PCP receptor through two distinct mechanisms. First, SPD, like glycine, increases the percentage of time that NMDA channels remain in the open state in the presence of L-glutamate, consistent with a role as a positive allosteric modulator of NMDA receptor activation. Second, unlike glycine, SPD increases the affinity of the PCP receptor for its ligands. The latter effect does not appear to reflect increased NMDA receptor activation. SPD does not induce glycine-like alteration of the EC50 value for stimulation of PCP receptor binding by L-glutamate, suggesting that the effects of SPD cannot be attributed solely to augmentation of glycine binding. These findings demonstrate first that total specific PCP receptor binding cannot, of itself, be used as an index of NMDA receptor activation and second, glycine and polyamines differ in the mechanisms by which they potentiate PCP receptor binding.
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PMID:Activation-related and activation-independent effects of polyamines on phencyclidine receptor binding within the N-methyl-D-aspartate receptor complex. 791 16

Binding of 1-[1-(2-[3H]thienyl)cyclohexyl]piperidine ([3H]TCP) to mouse brain and spinal cord membranes was studied using compounds selective for the NMDA-coupled 1-(1-phenylcyclohexyl)piperidine (PCP) and/or sigma recognition sites. In both tissues, [3H]TCP labeled two populations of binding sites. Density of the low-affinity sites was approximately the same in both tissues, but the population of the high-affinity [3H]TCP sites was three times bigger in the brain than in the spinal cord. Self- and cross-displacement studies showed that the high-affinity [3H]TCP binding sites could be identical with NMDA receptor-coupled PCP sites, whereas the low-affinity [3H]TCP sites may be associated with sigma binding sites in both tissues. The NMDA-coupled PCP sites labeled in the presence of 6.25 nM [3H]TCP constituted a much higher percentage of the total binding in the brain (75%) than in the spinal cord (44%). Consistent with this, reintroduction of glycine and glutamate significantly increased, but DA antagonists significantly inhibited [3H]TCP binding in the brain but not in the spinal cord. Together, these data suggest that a large component of [3H]TCP-labeled binding sites in the spinal cord may be associated with sigma but not the NMDA receptor-coupled PCP sites.
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PMID:Density of NMDA-coupled and uncoupled 1-[1-(2-[3H]thienyl) cyclohexyl]piperidine recognition sites in the brain and spinal cord: differential effects of NMDA agonists and antagonists. 793 31

IDDC (3, 10,5-(iminomethano)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene++ +) and a series of substituted derivatives were synthesized and evaluated in vitro for their ability to displace tritiated MK-801 ([3H]-2) from its specific binding site in guinea pig brain homogenate. Substitution at the 3-position of 3 with bromine, chlorine, and fluorine led to increased binding affinity. In contrast, substitution of donor groups at the 3-position gave decreased binding affinities, as did all substitutions at the 7-position and on nitrogen. Where racemic mixtures were resolved, the (+)-optical antipodes were more active than their enantiomers or racemates. The most active ligand found in this study was (+)-13e (IC50 = 15.5 +/- 4.5 nM). The affinity of (+)-13e for the PCP receptor makes it among the most potent ligands known. In vitro neuroprotection was demonstrated by 3, (+)-3, and (+)-6 (N-Me-IDDC) against glutamate-induced cell death in rat hippocampal cells.
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PMID:10,5-(Iminomethano)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and derivatives. Potent PCP receptor ligands. 810 72

A novel series of octahydrophenanthrenamines and their heterocyclic analogues have been synthesized as potential noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) receptor complex. The compounds were evaluated for their affinity at the phencyclidine (PCP) binding site by determining their ability to displace [3H]TCP from crude rat brain synaptic membranes. A wide range of affinities were observed, with the most potent analogs possessing IC50's equivalent to that of the reference agent MK-801 (3, dizocilpine). NMDA antagonist activity was demonstrated by prevention of glutamate-induced accumulation of [45Ca2+] in cultured rat cortical neurons. Selected compounds were also studied in vivo to determine their ability to prevent the lethal effects of systemically injected NMDA in the mouse. In general, the SAR of the phenanthrenamine series may be summarized as follows: (a) for the amino group at C4a, NHMe > NH2 > NHEt >> NC5H10; (b) for the B-ring substitution, X = CH2 > S > O; (c) unsaturation of the C ring decreases receptor affinity; (d) cis-ring fusion between the B and C rings is desirable; (e) 6-hydroxy or 6-methoxy substitution of the phenanthrenamine system identified an additional hydrogen bonding interaction that substantially increased receptor affinity; (f) spiro analogues (such as 55, IC50 = 3400 nM), which altered the point of attachment of the C ring, caused a substantial reduction in PCP-site affinity. Molecules from this series were useful for refining a pharmacophore model consistent with previous models of the PCP site. In this model, the (R)-(+)-phenanthrenamine 13 superimposes closely onto MK-801 (3), and the angular 4a-amino group is believed to hydrogen bond with a putative receptor site atom. In the phenanthrenamine and thiaphenanthrenamine series, the (R)-(+)-enantiomers (9, 13, and 44) are more potent by approximately 5-10-fold than their corresponding (S)-(-)-enantiomers with respect to their affinity for the PCP site, their ability to prevent accumulation of [45Ca2+] in cultured neuronal cells, and their protection against the lethal effects of NMDA in mice. In general, there was no separation between the dose that prevented NMDA lethality and the dose that produced ataxia in mice, except in the case of the thiaphenanthrenamines 41 and 43. We have not yet obtained evidence that this small separation in activity offers a therapeutic advantage in the treatment of cerebral ischemia or other neurodegenerative disorders.
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PMID:Synthesis and pharmacological evaluation of 4a-phenanthrenamine derivatives acting at the phencyclidine binding site of the N-methyl-D-aspartate receptor complex. 833 37

Consistent with the neuroprotective effects of the non-opioid antitussive dextromethorphan (DM) described in several models of CNS injury, micromolar concentrations of three novel analogs of DM markedly attenuated the injury produced by glutamate in cultured rat cortical neurons. Furthermore, the neuroprotective actions of the DM analogs correlated with their effects to block glutamate-induced excitotoxic calcium signals and were unrelated to metabolism to the phencyclidine (PCP)-like drug dextrorphan (DX). These observations establish a new class of compounds related to DM which, by virtue of their efficacy to protect neurons against a severe glutamate insult, may possess therapeutic potential as treatment modalities for a number of neurodegenerative diseases.
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PMID:Dextromethorphan analogs are neuroprotective in vitro and block glutamate-induced excitotoxic calcium signals in neurons. 859 46

The open channel N-methyl-D-aspartate (NMDA) receptor antagonists dizocilpine (MK-801) and phencyclidine (PCP) increase the firing rate of both A9 and A10 dopaminergic neurons in the rat. In the A10 nucleus, this effect of MK-801 is reportedly prevented by either competitive NMDA antagonists or serotonin2 (5-HT2) antagonists. The present study examined the neurochemical correlates of these effects using the technique of in vivo microdialysis in conscious rats. In contrast to its reported electrophysiological effects at the cell body level, MK-801 (2 mg/kg, i.p.) has divergent effects on dopamine release in the terminal fields of the A9 and A10 systems. MK-801 stimulated dopamine release in both the medial prefrontal cortex and the nucleus accumbens but tended to decrease release in the striatum. Stimulated dopamine release in the nucleus accumbens was selectively blocked by either the competitive NMDA receptor antagonist, MDL 100,453 or the 5-HT2A receptor antagonist, MDL 100,907. Neither MDL 100,453 nor MDL 100,907 affected MK-801-induced release in the medial prefrontal cortex. The results illustrate the complex regulation of the forebrain dopaminergic systems by glutamate and indicate that the serotonergic system, via the 5-HT2A receptor, may play an important role in this regulation.
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PMID:Regional effects of MK-801 on dopamine release: effects of competitive NMDA or 5-HT2A receptor blockade. 866 21

We have previously shown that a single dose of PCP produces a dose-related increase in NMDA-sensitive 3H-glutamate binding in CA1 of hippocampus 24 hours later, and some regional changes in kainate binding. Here we report that dizocilpine (MK 801) (0.1 mg/kg and 1 mg/kg), a selective agonist at the PCP receptor and a noncompetitive antagonist of NMDA, produces a similar increase in NMDA-sensitive glutamate and kainate receptor binding in hippocampus 24 hours after a dose. These observations support the conclusion that blockade of glutamate-mediated transmission at the NMDA receptor selectively increases NMDA-sensitive glutamate receptor binding in CA1 of hippocampus and kainate binding in CA3 and dentate gyrus at putatively delayed time points. Several additional areas outside of hippocampus also showed receptor changes at 24 hours after MK801.
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PMID:MK801 induces late regional increases in NMDA and kainate receptor binding in rat brain. 869 41

Amphetamine and related drugs of abuse facilitate dopamine transmission in the striatum. This action is believed to underlie the increase in firing of striatal motor-related neurons after amphetamine administration in behaving rats. The present study extended this electrophysiological investigation to phencyclidine (PCP), a nonamphetamine psychomotor stimulant that acts primarily as a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) glutamate receptors. Like amphetamine, PCP (1.0, 2.5, or 5.0 mg/kg) increased the activity of striatal motor-related neurons concomitant with behavioral activation. These effects were blocked by subsequent administration of either 1.0 mg/kg haloperidol or 20.0 mg/kg clozapine, typical and atypical neuroleptics, respectively. Dizocilpine (MK- 801), another noncompetitive NMDA antagonist, mimicked the effect of PCP. Collectively, these results indicate that amphetamine and NMDA antagonists exert comparable effects on striatal motor-related neurons, suggesting that the response of these cells to psychomotor stimulants is regulated by a dopaminergic-glutamatergic influence.
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PMID:Phencyclidine-induced increases in striatal neuron firing in behaving rats: reversal by haloperidol and clozapine. 874 75

Since unique calcium dynamics have been reported for toxic (40-80 M) and non-toxic (5-10 microM) concentrations of glutamate, we evaluated the effect of neuroprotective sigma ligands on glutamate and potassium chloride (KCl)-stimulated changes in [Ca2+]i using 12-15 day old primary rat neuronal cortical cultures. In approximately 80% of the neurons tested, 80 microM glutamate caused a sustained calcium flux previously shown to be associated with neurotoxicity. The majority of sigma ligands that were evaluated altered glutamate-induced calcium flux. For example, the primary effect of maximally neuroprotective concentrations of the sigma ligands dextromethorphan, (+)-pentazocine, (+)-cyclazocine, (+)-SKF 10047, carbetapentane and haloperidol was a shift from a sustained, to either a biphasic or a monophasic transient calcium response indicative of neuroprotection. (+)-3-PPP, previously shown not to be neuroprotective in this model system, failed to alter glutamate-induced calcium flux. In contrast to glutamate, KCl (50 mM) produced changes in [Ca2+]i which were not neurotoxic to the neurons as measured by LDH release. The primary response observed in 59% of the neurons treated with 50 mM KCl alone was an initial spike in [Ca2+]i which abruptly declined then plateaued above basal levels throughout the 12 min of analysis (modified sustained response). The highly selective sigma ligands produced a shift from the modified sustained response to a monophasic transient calcium response. Again, (+)-3-PPP had no effect on KCl-induced calcium dynamics. Of the PCP-related sigma ligands only (+)-SKF-10047 consistently attenuated the KCl-induced calcium flux. Collectively, these results indicate that modulation of [Ca2+]i through receptor and voltage-gated calcium channels contributes significantly to sigma mediated neuroprotection.
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PMID:Role of calcium in sigma-mediated neuroprotection in rat primary cortical neurons. 875 Sep 59


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