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 present study provides evidence for the presence of an endogenous ligand for the phencyclidine (PCP) receptor of mammalian brain. Partially purified bovine hippocampal extracts potently and dose dependently inhibit binding to PCP receptors of [3H]N-(1-[2-thienyl]-cyclohexyl)piperidine (TCP), a highly potent and specific ligand of PCP receptors. In addition to demonstrating PCP-like binding properties, the partially purified extract mimics biological actions of PCP upon neurotransmitter release. HPLC fractions active in the [3]TCP binding assay, by contrast to fractions inactive in the binding assay, potently elicited stimulation of spontaneous acetylcholine and dopamine efflux and inhibited NMDA-stimulated release of acetylcholine and dopamine. The transmitter release assay provides validation of a PCP-like physiological activity exerted by bovine hippocampal extracts partially purified by HPLC.
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PMID:An endogenous ligand of the brain sigma/PCP receptor antagonizes NMDA-induced neurotransmitter release. 288 50

N-Methyl-D-aspartate (NMDA) stimulated (EC50 = 19.4 +/- 1.9 microM) gamma-aminobutyric acid (GABA) release from highly purified striatal neurones differentiated in primary culture. NMDA effect was inhibited (i) in a competitive manner by DL-2-amino-5-phosphonovalerate (APV) and (ii) in a non-competitive manner by phencyclidine (PCP). Kainate (KA) also stimulated GABA release, but this effect was never inhibited by PCP despite the multiple conditions tested (KA stimulation performed, after or not NMDA application, in the presence or not of NMDA). The existence of two distinct receptor-channel complexes on striatal neurones selectively activated by NMDA and KA is discussed.
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PMID:NMDA- and kainate-evoked GABA release from striatal neurones differentiated in primary culture: differential blocking by phencyclidine. 289 15

2-Amino-5-phosphonovalerate (APV, icv) phencyclidine (PCP, ip) and scopolamine (sc) dose-dependently disrupted short term working memory in radial maze. These drugs injected before, but not after training attenuated retention of long term memory in passive avoidance task. A relation of PCP action to its antagonism at NMDA receptors may be suggested.
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PMID:Learning impairment in rats by N-methyl-D-aspartate receptor antagonists. 290 78

The analgesic efficiency of ketamine and pethidine was compared in experimental ischemic pain and postoperative pain after oral surgery. Naloxone 1.6 mg or placebo was given 5 min before the analgesic drug. The subjects recorded their pain on a visual analogue scale. Both ketamine 0.3 mg/kg and pethidine 0.7 mg/kg were effective as analgesics against the two types of pain studied. Naloxone prevented the analgesic effect of pethidine, but had no effect on ketamine analgesia. The results are in accordance with the hypothesis that the analgesic effect of ketamine is mediated by a non-opioid mechanism, possibly involving PCP-receptor-mediated blockade of the NMDA-receptor-operated ion channel.
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PMID:Comparison of ketamine and pethidine in experimental and postoperative pain. 291 93

N-Methyl-D-aspartic acid (NMDA) produced a dose-related increase in lethality in mice, with 200 mg/kg (i.p.) effecting 100% lethality. Upon daily dosing, acutely sublethal doses of NMDA produced deaths. This NMDA-induced lethality was stereoselective; N-methyl-L-aspartic acid had no effects at doses as high as 400 mg/kg. Moderate doses of phencyclidine (PCP) and drugs having PCP-like behavioral effects blocked the NMDA-induced lethality. Other classes of psychoactive drugs, including opioids, anticonvulsants and antipsychotics, were ineffective in preventing NMDA-induced lethality. The potency of PCP-like drugs to block the NMDA-induced lethality correlates highly with the dose necessary to produce PCP-like catalepsy and PCP-like discrimination in pigeons. These data support the hypothesis that PCP-like drugs produce many of their effects by impairing the normal functioning of the NMDA-defined excitatory neurotransmitter receptor in the central nervous system.
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PMID:N-methyl-D-aspartic acid-induced lethality in mice: selective antagonism by phencyclidine-like drugs. 329 8

The present study was undertaken to determine the role and modulation of the PCP/NMDA receptor complex and sigma binding sites in the central nervous system of animals treated with psychostimulant agents. Repeated exposure of mice to cocaine (45 mg/kg/day; for 7 days) was associated with a progressive increase in convulsive response and lethality rate. The sensitization to the toxic effects of cocaine in mice was completely abolished by pretreatment with either the noncompetitive NMDA receptor antagonist MK-801 (0.35 mg/kg/day), or the nitric oxide synthase inhibitor Ng-nitro-L-arginine methyl ester (100 mg/kg/day). Parallel in vitro receptor binding assays indicated first, upregulation of cortical NMDA receptors labeled with [3H]CGP 39653, and second, glutamate-dependent sensitization of [3H]MK-801 binding to the PCP site in cortical membranes of the mice treated for 7 days with cocaine. Repeated exposure of rats to methamphetamine (4.0 mg/kg/day; for 10 days) resulted in a significant upregulation of the sigma-1 binding site labeled with (+)[3H]pentazocine in the frontal cortex and substantia nigra. The cocaine-related studies suggest that the PCP/NMDA receptor complex is involved in the development of sensitization to the neurotoxic effects of the drug, such as "pharmacological kindling". The methamphetamine-related studies insinuate a potential role of sigma-1 binding sites in psychostimulant-induced behavioral disorders.
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PMID:Modulation of the PCP/NMDA receptor complex and sigma binding sites by psychostimulants. 752 45

Phencyclidine (PCP) acts on a variety of neurotransmitter systems--cholinergic, catechoaminergic, indoleaminergic, and peptidergic--but the dose at which it produces its psychotomimetic effects is lower than the concentration at which it affects these systems. At low doses, PCP interacts primarily with a binding site located within the ionophore associated with the NMDA receptor complex--binding to this site has been used as a biochemical marker for NMDA channel activity. PCP/NMDA receptor-channel complex has been shown to play an important role in brain development but little is known of the neurochemical effects following postnatal administration of NMDA antagonists in rats. In the present study, rats were treated with PCP from Day 5 until Day 15 after birth and binding to the PCP receptor was measured on postnatal Day 21 using [3H]MK-801; MK-801 is a more potent and specific ligand at the PCP receptor than PCP itself. Postnatal PCP administration produced specific alterations in PCP receptor binding in 21-day-old rat forebrain. There was a reduction in the high affinity component of [3H]MK-801 binding under baseline binding conditions. In the presence of both L-glutamate and glycine, [3H]MK-801 binding in PCP-treated rats increased significantly compared to baseline but did not differ from saline-treated controls. These findings suggest that chronic PCP administration in developing rats alter NMDA channel functioning which could have long-term neurobehavioral consequences.
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PMID:PCP/NMDA receptor-channel complex and brain development. 752 46

A series of novel N-methyl-D-aspartate antagonists acting at the phencyclidine site has been identified. Compound 2 has a Ki = 8 +/- 1 nM (vs [3H]thienylcyclidine, [3H]TCP) as a mixture of enantiomers. Resolution and further testing indicate that (-)-2, Ki = 4 +/- 0.7 nM, is a potent and selective TCP site ligand with neuroprotective activity in cultured neurons in the presence of excitotoxic concentrations of NMDA (IC50 = 26 nM). Compound (-)-2 is > 1000-fold selective for the TCP site vs a panel of receptor types including opiate, adrenergic, serotonergic, dopamine, adenosine, dihydropyridine, and benzodiazepine and displays increased selectivity for the activated (open) NMDA receptor-ion channel complex vs PCP and MK801 as measured by patch recordings in cultured, voltage-clamped neurons. Highly enhanced "open-channel" selectivity leads to tentative classification of these ligands as uncompetitive vs NMDA. Ligands with these characteristics may enable deconvolution of the pharmacologic effects associated with typical noncompetitive NMDA antagonists. We report here on the identification, synthesis, and activity of compounds of this structural class.
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PMID:Identification, synthesis, and characterization of a unique class of N-methyl-D-aspartate antagonists. The 6,11-ethanobenzo[b]quinolizinium cation. 752 82

In order to clarify the roles of the hippocampal sigma site and phencyclidine (PCP) binding site on the NMDA receptor/channel complex in the regulation of working memory in rats, the effects of intrahippocampal administration of ligands for both binding sites on this behavior were examined with a three-panel runway task. MK-801, a potent noncompetitive NMDA antagonist with high affinity for the PCP site, significantly increased the number of working memory errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points), when injected bilaterally at 0.1 and 0.18 microgram/side into the dorsal hippocampus. However, intrahippocampal injection of (+)-SKF 10,047, a sigma ligand, at doses up to 1.0 microgram/side had no significant effect on the number of working memory errors. The working memory impairment induced by intrahippocampal MK-801 (0.18 microgram/side) was attenuated by concurrent injection of 1.0 microgram/side (+)-SKF 10,047, but not by that of 1.0 microgram/side (-)-SKF 10,047. These results suggest that activation of hippocampal sigma and PCP binding sites exerts antagonistic effects on working memory function, possibly through modulation of NMDA receptor-mediated glutamatergic neurotransmission.
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PMID:Intrahippocampal administration of (+)-SKF 10,047, a sigma ligand, reverses MK-801-induced impairment of working memory in rats. 758 31

The purpose of the present studies was to examine representative uncompetitive and competitive NMDA antagonists, as well as the glycine/NMDA antagonist, HA 966, in pigeons trained to discriminate either PCP or CGS 19755 from saline. Separate groups of pigeons were trained to discriminate either the uncompetitive, phencyclidine (PCP; 0.32 and 1.0 mg/kg, IM), or the competitive, CGS 19755 (cis-4-phosphonomethyl-2-piperidine-carboxylic acid; 1.8 mg/kg, IM), NMDA antagonists from saline. Uncompetitive and competitive NMDA antagonists were examined in generalization studies, as were the racemate and the (+) and (-) stereoisomers of HA 966 (3-amino-1-hydroxypyrrolid-2-one). Dizocilpine (MK 801) was fully generalized to PCP but not to CGS 19755. All competitive NMDA antagonists tested were fully generalized to CGS 19755, but not to PCP. The competitive antagonists, however, produced > 50% PCP-appropriate responding. The (+) isomer of HA 966 was fully generalized by three of four pigeons discriminating PCP (1.0 mg/kg) or CGS 19755, whereas the racemate and the (-) isomer produced < 40% drug-appropriate responding in either group. Neither NMDA, morphine, nor pentobarbital produced > 10% drug-appropriate responding in either discrimination group. The competitive antagonists tended to produce peak drug-appropriate responding at times greater than 60 min after administration, whereas uncompetitive antagonists produced peak drug-appropriate responding at earlier times. HA 966 also had a relatively slow onset of action as compared to PCP. These results suggest that antagonists acting at different modulatory sites of the NMDA receptor complex produce similar, but not identical, discriminative stimuli.
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PMID:Competitive and uncompetitive N-methyl-D-aspartate antagonist discriminations in pigeons: CGS 19755 and phencyclidine. 759 21


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