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 effects of dizocilipine (MK-801), (+/-)-5-methyl-10,11-dihydro-5Hdibenzo-[a,d]-cyclohepten-5, 10-imine maleate, after IP injection into freely behaving rats, have been compared with the action of ketamine-chloride and phencyclidine (PCP). MK-801 produced strongly dose-dependent effects which could be followed quantitatively over a time of 4 h. During this time spectral analysis of the field potentials continuously recorded from frontal cortex, hippocampus, striatum, and reticular formation revealed a particular pattern of changes which was very stable over time, and after low doses of 0.05 and 0.1 mg/kg, matched that produced by phencyclidine (2 and 4 mg/kg) or ketamine chloride (10 and 20 mg/kg). With higher doses of MK-801 a continuous change from power decreases to power increases was observed. These increases were accompanied by strong behavioral effects in terms of impaired locomotor control. All three non-competitive NMDA antagonists showed a high degree of similarity with respect to the changes of the frequency content of the field potentials over time. The same pattern of electrical changes could be observed after the application of L-dopa (50 mg/kg) or amphetamine (0.2 mg/kg). This can be interpreted in the sense that the same population of cells within the recording area which is under dopaminergic control is at the same time under glutamate control. This leads to the hypothesis that it might be possible to bypass the missing dopaminergic control during parkinsonism by noncompetitive NMDA-receptor blocking drugs.
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PMID:Dizocilpine (MK-801), ketamine and phencyclidine: low doses affect brain field potentials in the freely moving rat in the same way as activation of dopaminergic transmission. 216 37

Ketamine has been employed as an anesthetic for 25 years. It is the only PCP-like dissociative anesthetic in clinical use. Favourable experience with ketamine in combat situations and at accidents, together with its ability to block the effect of the excitatory neurotransmitter glutamate on NMDA-receptor mediated neurotransmission, has attracted greater attention to this drug in recent years. The indications for and the use of ketamine as an anesthetic is described, and its various side-effects discussed. Combination with benzodiazepines greatly reduces these side-effects. Several pharmacological mechanisms may contribute to the effects of ketamine, in particular when large (anesthetic) doses are given. Recent investigations indicate that the analgesic and anesthetic effects as well as the "dissociative" phenomena seen after analgesic doses are due to PCP receptor mediated inhibition of excitatory amino acid transmission at NMDA synapses. The excitatory effect observed at higher doses, however, may be mediated by the haloperidol sensitive sigma-receptor. The enantiomers of ketamine (R- and S-ketamine) differ in pharmacological profile and may enable improvement of ketamine as a drug.
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PMID:[Ketamine: clinically useful--pharmacologically interesting]. 216 88

In functional studies, phenycyclidine (PCP) and similar drugs non-competitively antagonize neuronal responses to the excitatory amino acid, N-methyl-D-aspartate (NMDA). Here we show that, in crude postsynaptic densities from rat brain, the binding of [3H]TCP (a PCP analogue) was enhanced almost 4-fold by L-glutamate and NMDA, but not by quisqualate, kainate or gamma-aminobutyric acid. The potencies of excitatory amino acid agonists and antagonists in the [3H]TCP binding assay closely paralleled their affinities for NMDA-sensitive L-[3H]glutamate binding sites. In contrast, dissociative anaesthetics and sigma-opiates inhibited [3H]TCP binding (with a profile characteristic of PCP binding sites), but had no effect on L-[3H]glutamate binding. These data indicate that PCP binding sites are linked to NMDA receptors, and that PCP and related drugs bind preferentially to the activated configuration of the NMDA receptor channel complex.
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PMID:Phencyclidine and related drugs bind to the activated N-methyl-D-aspartate receptor-channel complex in rat brain membranes. 243 6

The effects of agonists of the N-methyl-D-aspartate (NMDA) receptor can be blocked by dissociative anesthetics such as phencyclidine (PCP) in a non-competitive manner. This finding together with the fact that ligand binding to the PCP receptor is dependent on the presence of L-glutamate has led to the suggestion that there may exist an NMDA/PCP receptor complex in mammalian brain tissue. This concept has been extended to the inclusion of a cation channel based on the inhibitory actions of the divalent cation, magnesium. Evaluation of the binding of tritiated TCP (thienylcyclohexylpiperidine) a high affinity ligand for the PCP receptor, under four conditions: in basal, well washed rat cortical membranes; in the presence of L-glutamate; in the presence of magnesium; and in the presence of both magnesium and L-glutamate, with NMDA antagonists and dissociative anesthetics showed that these agents had distinct profiles of activity at the PCP receptor. Furthermore, while both classes of compound could modulate TCP binding, only NMDA receptor antagonists inhibited the binding of tritiated CPP (3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid) which labels central NMDA recognition sites. The present data support the existence of an NMDA/PCP receptor complex in mammalian brain tissue. The data currently available would suggest however, that the interface is sequentially NMDA to PCP with the latter site affecting NMDA-mediated responses at a step intermediate between receptor activation and physiological response.
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PMID:The N-methyl-D-aspartate receptor complex. 245 46

The phencyclidine (PCP) receptor is a site within the ion channel gated by the N-methyl-D-aspartate (NMDA)-type excitatory amino acid receptor. In the present study, kinetics of association and dissociation of the specific PCP receptor ligand [3H]MK-801 were determined in order to elucidate the mechanism of functioning of the NMDA receptor complex. Two distinct components of [3H]MK-801 association with apparent t1/2 values of approximately 10 min and 3 hr were resolved. Incubation with the NMDA receptor agonist L-glutamate increased the total steady state binding of [3H]MK-801 and increased the relative percentage of [3H]MK-801 binding that manifested fast rather than slow kinetics, without altering the observed rate constant of either the fast or slow component of association. The competitive NMDA receptor antagonist D(-)-2-amino-5-phosphonovaleric acid decreased total steady state binding of [3H]MK-801. These data support a model in which [3H]MK-801 can gain access to its binding site via two distinct paths, a fast hydrophilic path associated with a conformation of the NMDA receptor in which the channel is open and a slow hydrophobic path independent of the open channel. In the presence of L-glutamate, incubation with glycine increased the relative percentage of [3H]MK-801 binding that manifested fast rather than slow kinetics. The Hill coefficient for stimulation of specific [3H]MK-801 binding by L-glutamate was significantly greater than unity in either the absence or presence of glycine. Our data support a model of NMDA receptor functioning in which two molecules of agonist are required to convert the receptor complex to a conformation that is in equilibrium with the open conformation and in which glycine regulates the percentage of NMDA receptor complexes bound to two molecules of agonist that convert to the open configuration.
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PMID:Biexponential kinetics of [3H]MK-801 binding: evidence for access to closed and open N-methyl-D-aspartate receptor channels. 246 76

In rats receiving N-methyl-D-aspartate (NMDA) intraventricularly or intracisternally the cerebellar cyclic guanosine monophosphate (cGMP) content increases in a dose-related manner. This response was used to study phencyclidine (PCP) and glycine interactions with the glutamate receptor subtype stimulated by NMDA. The increase of cGMP elicited by NMDA was inhibited by PCP and potentiated by glycine. Moreover, 2-amino-5-phosphonovalerate (APV) abolished the NMDA response. Since the increase in cerebellar cGMP induced by kainate, a synthetic agonist of another glutamate receptor subtype, was not modified by APV, the specificity of its action on NMDA response was confirmed. The increase of cerebellar cGMP content elicited by glycine was inhibited by PCP and APV but not by strychnine. Binding studies failed to demonstrate an apparent competitive interaction between PCP, glycine and NMDA. This suggests that the observed interaction is not of the isosteric type. The present results provide evidence that glycine, in vivo, acting at strychnine-insensitive recognition sites modulates allosterically in a positive manner the function of NMDA-sensitive glutamate receptors.
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PMID:Modulation of glutamate receptors by phencyclidine and glycine in the rat cerebellum: cGMP increase in vivo. 253 9

The distribution of [3H]glycine binding sites was compared with that of N-methyl-D-aspartate (NMDA) receptors labelled with L-[3H]glutamate, and with that of phencyclidine (PCP) receptors labelled with [3H]1-(1-(2-thienyl)-cyclohexyl)piperidine ([3H]TCP) in sections from 7 normal human hippocampi. The results indicate that strychnine-insensitive glycine binding sites are present in high concentrations in CA1 and the molecular layer of the dentate gyrus. This distribution is very similar to the distributions of NMDA and PCP receptors in the human hippocampus.
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PMID:[3H]glycine binding sites, NMDA and PCP receptors have similar distributions in the human hippocampus: an autoradiographic study. 253 83

The effects of non-NMDA receptor agonists were tested on endogenous GABA and [3H]GABA release from highly purified striatal neurons differentiated in primary culture. Kainate (KA), glutamate (Glu) and quisqualate (QA) stimulated [3H]GABA release with EC50S = 85 +/- 20 (n = 6), 6.21 +/- 1.42 (n = 3) and 0.135 +/- 0.035 (n = 3) microM, respectively. KA was the most potent (in term of efficacy) agonist (maximal response at 10 mM: 935 +/- 51% (n = 6) increase over basal release) followed by Glu (at 100 microM: 404 +/- 34% (n = 5) increase) and QA (at 10 microM: 91 +/- 6% (n = 6) increase). Phencyclidine (PCP), which was without effect on QA- and KA-evoked GABA release, inhibited the Glu response by about 50%. QA totally inhibited KA (50 microM)-evoked GABA release with an IC50 = 0.39 +/- 0.11 (n = 4) in a competitive manner (Ki = 0.39 +/- 0.07 microM (n = 3]. Competitive inhibition of the KA response was also observed with the other agonists of the quisqualate receptor, Glu and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), suggesting that Glu, QA and AMPA act as partial agonists at the KA receptor. gamma-D-Glutamylaminomethylsulfonic acid (GAMS) also inhibited (IC50 = 2.1 mM) the KA response competitively. However the inhibition by GAMS and QA was not additive. The response to QA was rapidly inactivated (no response after 3 min stimulation) in contrast to the KA-evoked GABA release which remained maximal for at least 3 min. When neurons were first exposed to concanavalin A (con A), a lectin known to inhibit Glu receptor desensitisation on insect muscles, the QA response remained maximal for at least 6 min. Con A greatly enhanced the maximal responses to QA and AMPA and decreased their apparent affinities. The KA-evoked GABA release (but not the veratridine and NMDA effects) was also augmented (no change in the EC50 value) by con A. It is proposed that QA, AMPA and KA act at the same receptor-channel complex (termed G2 receptor) which is desensitised more rapidly when stimulated by QA or AMPA than when stimulated by KA.
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PMID:Complex interaction between quisqualate and kainate receptors as revealed by measurement of GABA release from striatal neurons in primary culture. 254 Oct 1

Rapid vacuum filtration assays were used to quantitate radioligand binding to phencyclidine (PCP), N-methyl-D-aspartate (NMDA), and strychnine-insensitive glycine receptors in a simple buffy coat preparation of rat cortical membranes. KD and Bmax values for [3H]glycine binding were very similar to those previously reported by workers who used centrifugation for the separation of free and bound [3H]glycine. We also found that this preparation had a high percentage of NMDA-displaceable L-[3H]glutamate binding sites, which demonstrated a pharmacology very similar to that previously observed in more purified synaptic plasma membranes. Hill analysis of the displacement curves indicated that glutamate bound to a single class of sites, but that NMDA and NMDA antagonists may interact with this site in a negatively cooperative fashion. This preparation was also found to be suitable for the study of NMDA and glycine receptor regulation of the associated ion channel, as these effectors, alone and in combination, increased the affinity with which [3H]TCP bound to the PCP receptor believed to be located within the ion channel. Thus, the ability to measure radioligand binding to these three sites in the same simple membrane preparation should greatly facilitate the study of the interaction between them.
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PMID:Characterization of the binding of radioligands to the N-methyl-D-aspartate, phencyclidine, and glycine receptors in buffy coat membranes. 254 Dec 83

Release of both D-[3H]aspartate and endogenous amino acids was measured in primary cultures of cerebellar granule cells. Two hour-pretreatment with the glycosphingolipids, GM1 or GT1b, attenuated the stimulation of excitatory amino acid release induced by depolarizing concentrations of K+ (50 mM). Gangliosides inhibited the phencyclidine (PCP)-sensitive component of depolarization-induced release, i.e. the amplification of release that follows activation of NMDA receptors by the endogenous glutamate.
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PMID:Gangliosides attenuate NMDA receptor-mediated excitatory amino acid release in cultured cerebellar neurons. 255 58


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