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)

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

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

Measurements of calcium uptake and cyclic GMP production by cerebellar granule cells grown in primary culture demonstrated that ethanol preferentially inhibited N-methyl-D-aspartate (NMDA) receptor-gated cation channel function. Concentrations of ethanol as low as 10 mM inhibited NMDA-stimulated Ca2+ uptake by greater than 30%, and ethanol also inhibited NMDA-stimulated (Ca2+-dependent) cyclic GMP accumulation in a similar, dose-dependent manner. Responses to kainate were significantly less sensitive to ethanol. Studies using various concentrations of NMDA, as well as phencyclidine (PCP) and glycine, suggested that ethanol affected the "coagonist" binding site of the NMDA receptor-channel complex, rather than the PCP recognition site.
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PMID:N-methyl-D-aspartate receptors and ethanol: inhibition of calcium flux and cyclic GMP production. 254 53

1. As reported for many other PCP receptor actions, the pharmacological profile of PCP receptor agonists and NMDA receptor antagonists were similar with regard to their effects on cerebellar cGMP levels in vivo. 2. PCP receptor agonists act to increase mesocortical dopamine (DA) metabolism and release. 3. This receptor action is stereospecific and is both dose- and time-dependent. 4. The actions of PCP on DA metabolism appear to involve PCP receptors both in the ventral tegmental area (VTA) and the cortical nerve terminal regions. 5. In contrast to many other systems which have been studied, competitive NMDA antagonists do not act in a manner similar to PCP agonists, with regard to mesocortical DA metabolism. 6. Sigma receptor ligands and NMDA agonists also do not alter mesocortical DA metabolism. 7. These data suggest that the PCP receptor population which modulates mesocortical dopaminergic neurons is not coupled to NMDA receptors.
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PMID:NMDA-coupled and uncoupled forms of the PCP receptor: preliminary in vivo evidence for PCP receptor subtypes. 254 81

The high pressure neurological syndrome (HPNS) occurs when man or animals are exposed to hyperbaric pressure. Four non-competitive N-methyl-D-aspartate (NMDA) antagonists - MK-801, phencyclidine (PCP), SKF 10,047 and ketamine were tested in rats for effects on the HPNS. All drugs were injected i.p. prior to compression; ketamine was also infused i.v. Control rats received saline. Rats were exposed individually to increasing helium pressure (PO2 0.5 atmospheres absolute ATA). Three endpoints were used to assess HPNS: onset pressures for tremor, myoclonus and convulsions. Neither MK-801 (0.03 and 0.3 mg/kg) nor SKF 10,047 (50 mg/kg) had any effect on the onset pressures for tremor, myoclonus or convulsions, although the type of seizure was modified from the clonic/tonic seizure seen in controls to purely clonic. PCP (5 mg/kg) had no effect on the endpoints, but pressure enhanced the excitation and stereotypy seen at 1 ATA. Ketamine (100 mg/kg i.p.) did not affect tremor or myoclonus; ketamine infused i.v. at pressure only prevented tremor and myoclonus at 'anaesthetizing' concentrations. Our results show that these non-competitive NMDA antagonists had little effect on HPNS, in contrast to competitive NMDA antagonists, such as AP7, which are highly effective. Possible explanations for this lack of effect include (1) interactions with NMDA receptor channels are pressure dependent; (2) other actions of these antagonists override their effects on the NMDA receptor channel.
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PMID:The effects of non-competitive NMDA receptor antagonists on rats exposed to hyperbaric pressure. 254 78

The selective non-competitive NMDA receptor antagonist, MK-801, potently blocked convulsions induced in the mouse by N-methyl-DL-aspartic acid (NMDLA) with an i.v. ED50 dose of 0.2 mg/kg. Similar doses of MK-801 were also effective in blocking seizures induced by pentylenetetrazol (PTZ), electroshock and by sound in audiogenic seizure-prone animals. Other less selective non-competitive NMDA receptor antagonists including phencyclidine (PCP), thienylcyclohexylpiperidine (TCP), (+)-N-allylnormetazocine [+)-NANM, (+)-SKF 10,047) and ketamine also blocked NMDLA-induced seizures with a rank order of potency of MK-801 greater than PCP greater than TCP = (+)-NANM greater than ketamine. The competitive NMDA receptor antagonist, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) blocked NMDLA-induced seizures with an ED50 of 4.5 mg/kg, 22- and 560-fold more potently than the competitive antagonists, 2-DL-amino-7-phosphonoheptanoic acid (2-APH) and 2-DL-amino-5-phosphonovaleric acid (2-APV), respectively. MK-801 was the most potent of the non-competitive antagonists to induce a motor syndrome including head weaving, body rolling, increased locomotion and ataxia, characteristic of the behavioural response to PCP in the mouse. The syndrome was also present following injection of the competitive NMDA receptor antagonists, although they were generally less potent (probably a reflection of poor brain penetration) and less efficacious than the non-competitive antagonists. For all compounds except CPP, the anticonvulsant ED50 dose was close to the minimum effective dose to induce motor stimulation: CPP was 5- to 10-fold more potent as an anticonvulsant.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The behavioural effects of MK-801: a comparison with antagonists acting non-competitively and competitively at the NMDA receptor. 255 Feb 53

7-Chlorokynurenic acid (7-Cl KYNA) has been reported to attenuate N-methyl-D-aspartate (NMDA) receptor functioning by a potent and selective inhibitory action mediated at the strychnine-insensitive glycine recognition site of the NMDA complex. Here we report that 7-Cl KYNA dose-dependently inhibits [3H]MK-801 binding to the PCP receptor, and that this effect is reversed by addition of glycine. Since [3H]MK-801 binding is a measure of channel activation, our results are consistent with the hypotheses that 7-Cl KYNA exerts its NMDA receptor antagonism by acting at the glycine site, and that activation of the glycine site is required for NMDA channel activity to occur.
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PMID:Glycine reverses 7-chlorokynurenic acid-induced inhibition of [3H]MK-801 binding. 255 30

The anticonvulsant activity of two competitive antagonists of the N-methyl-D-aspartate (NMDA) receptor, 2-amino-7-phosphonoheptanoic acid (APH) and 3-[2-carboxypiperazin-4-yl]-propyl-1-phosphonate (CPP), and two non-competitive NMDA antagonists, phencyclidine (PCP) and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801), were compared in 4 models of induced seizures in mice. All 4 drugs protected against tonic extensor seizures induced by pentylenetetrazol (PTZ), by submaximal (15 mA) electroconvulsive shock (ECS) and by maximal (50 mA) ECS. Similar orders of potency (i.e., MK-801 greater than PCP greater than or equal to CPP greater than APH) were seen in each of the 3 seizure models. All 4 drugs failed to block clonic seizures induced by picrotoxin in the dose ranges that protected from tonic seizures. These data are consistent with other data demonstrating that competitive and non-competitive NMDA antagonists have similar pharmacologic effects. These results also support the suggestion that the anticonvulsant effects of competitive and non-competitive NMDA antagonists are mediated by the NMDA receptor-ionophore complex.
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PMID:A comparison of the anticonvulsant effects of competitive and non-competitive antagonists of the N-methyl-D-aspartate receptor. 255 75


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