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)

SDZ EAA 494 (D-CPPene) was characterized as a competitive NMDA antagonist, having a pA2 value against NMDA depolarizations in frog spinal cord and rat neocortex of 6.7-6.8 and a pKi of 7.5 in a [3H]CGP39653 binding assay, with no action on other receptors or amine reuptake. The compound was orally active in rodent maximal electroshock models with an ED50 of around 16 mg/kg, was protective in rats even 24 hours after oral application and had an oral therapeutic index of around 8. Muscle relaxation, ataxia, flattened body posture and reduced acquisition of a passive avoidance task, suggesting potential effects on memory formation, occurred at supra-anticonvulsant doses in rodents, with PCP-like stimulatory effects produced only by high i.p. doses or constant i.v. infusions. This favourable profile is discussed in relation to the negative outcome of a recent trial of the compound in patients with intractable epilepsy. The conclusion is drawn that standard models for screening new anticonvulsants are inappropriate to seeking drugs active in patients with a protracted convulsive history. The anti-ischaemic action of SDZ EAA 494 encourages further testing in brain trauma, in which the anticonvulsant action of the compound may be an added benefit.
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PMID:The pharmacology of SDZ EAA 494, a competitive NMDA antagonist. 789 35

A putative animal model of anxiety based on shock-induced ultrasonic vocalization was pharmacologically validated in young adult rats. Suppression of shock-induced ultrasonic vocalization was obtained with diazepam, chlordiazepoxide, meprobamate and pentobarbital; the serotonin (5-HT)1A receptor agonists 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin], buspirone, ipsapirone, gepirone and tandospirone; the nonselective 5-HT receptor agonists TFMPP [1-(3-trifluoromethylphenyl)piperazin], mCPP [1-(3-chlorophenyl)piperazin] and DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane); the NMDA antagonists PCP (phencyclidine) and MK-801; the alpha 2-adrenoceptor antagonists idazoxane, yohimbine and 1-PP (1-pyrimidinylpiperazine); and the atypical neuroleptic clozapine. The alpha 2-adrenoceptor agonist clonidine, the 5-HT2/5-HT1C antagonist ritanserin, the 5-HT3 antagonists ondansetron and ICS-205,930, and the 5-HT reuptake inhibitor fluoxetine did not, or only partially, reduce ultrasonic vocalization. Tricyclic and tetracyclic, as well as some atypical antidepressants and a monoamineoxidase (MAO) inhibitor, showed no ultrasonic vocalization reducing effects, or reduced ultrasonic vocalization only at high doses. An opiate, an antimuscarinic, (pro)convulsants and typical neuroleptics did not reduce ultrasonic vocalization. The present findings suggest that the ultrasonic vocalization model specifically measures anxiolytic effects. Because ultrasonic vocalization responding develops within five days, remains stable for at least three months and gives highly reproducible results, the test appears suitable for rapid and repeated testing of new anxiolytics in the same animals.
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PMID:Shock-induced ultrasonic vocalization in young adult rats: a model for testing putative anti-anxiety drugs. 790 65

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

Locomotor activity, ataxia, and stereotypy were assessed in the open field after administration of NMDA and AMPA antagonists acting by different mechanisms. The interaction with glutamatergic receptors was confirmed in the binding assay. (+)MK-801 and phencyclidine (PCP) produced similar changes in horizontal activity, i.e., a strong increase from the beginning of the test. Ketamine, and to a lesser extent, memantine, enhanced horizontal activity at the later observation periods only. Amantadine and NBQX produced a slight inhibition, while GYKI-52466, d-cycloserine, (+R)-HA-966, CGP-37849, and dextromethorphan were ineffective. Vertical activity (rearings) were inhibited by most agents except GYKI-52466 and gly-B partial agonists. At higher doses ataxia was seen after: MK-801, PCP, ketamine, memantine, amantadine, CGP-37849, dextromethorphan, and GYKI-52466. Hence, the inhibition of NMDA and AMPA receptors by agents acting at different recognition sites produces qualitatively different behavioral consequences.
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PMID:Glutamate antagonists have different effects on spontaneous locomotor activity in rats. 802 81

Rats were trained to discriminate a dose of 1.75 mg/kg phencyclidine (PCP) from saline. During substitution tests, both PCP (0.3-10.0 mg/kg) and the non-competitive NMDA antagonist, MK-801 (0.01-0.3 mg/kg) substituted for the PCP stimulus in a dose-dependent manner. In contrast, delta 9-tetrahydrocannabinol (delta 9-THC, 0.1-5.6 mg/kg) and delta 8-tetrahydrocannabinol (delta 8-THC, 0.3-5.6 mg/kg) failed to substitute for the PCP stimulus, up to doses that substantially decreased rate of responding. However, both delta 9-THC and delta 8-THC partially attenuated the discriminative stimulus effects of the PCP training dose. Furthermore, a dose of 3.0 mg/kg delta 9-THC shifted the PCP dose-effect curve for discriminative stimulus effects to the right and shifted the PCP dose-effect curve for rate of responding to the left. The attenuation of the PCP stimulus by delta 9-THC lacked a strong dose-dependent relationship and was observed both at doses which did not alter rate of responding, as well as at doses which substantially decreased rate. In contrast to the effects observed with delta 9-THC and delta 8-THC, morphine, d-amphetamine and chlordiazepoxide failed to attenuate the discriminative stimulus effects of PCP, even at doses that markedly decreased rate of responding. The present findings suggest that delta 9-THC and delta 8-THC alter the discriminative stimulus effects of PCP in a pharmacologically specific manner.
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PMID:Discriminative stimulus effects of phencyclidine: pharmacologically specific interactions with delta 9- and delta 8-tetrahydrocannabinol. 805 36

The amin- and phenyl substituted 6,8-dioxabicyclooctanes 10 and 11 show distinct CNS-activities. Intensity and profile depend on the type of amine and the stereochemistry of the products. Therefore, we have synthesized 6,8-dioxabicyclooctanes with different amine-phenyl distances and examined their CNS-activities on mice as well as by receptor binding studies with the PCP-binding site which is part of the NMDA-receptor-complex.
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PMID:[CNS-active pyrans: amine- and aryl- substituted dioxabicyclooctanes]. 807 12

To determine the role of NMDA receptor blockade and sigma receptors in the behavioral effects of PCP during development, we assessed the behavioral effects of PCP, (+)-MK-801 and 1,3-Di(2-tolyl)guanidine (DTG) in preweanling rats. In the first experiment, rats were injected sc on postnatal day (PND) 19 with 0.5-4.5 mg/kg PCP, and locomotor activity and wall climbing behavior were scored. PCP induced high levels of locomotor activity on PND 19 in a dose dependent manner with the 2.0 mg/kg dose producing the greatest activity. In the second experiment, rats were injected on PND 12 or 19 with 1.0-4.0 mg/kg PCP or 0.1-0.4 mg/kg (+)-MK-801 and tested using the same procedures. Both PCP and (+)-MK-801 induced activity increases on PND 19 in a dose dependent manner, with 2.0 and 3.0 mg/kg PCP and 0.2 mg/kg (+)-MK-801 inducing the highest activity levels. Peak activity levels on PND 12 were approximately 30% of those observed on PND 19, with the lowest dose of PCP and (+)-MK-801 producing the greatest activity. Large amounts of wall climbing behavior were elicited by PCP on PND 12, whereas (+)-MK-801 induced only minor amounts of wall climbing. In the third experiment, the effects of 0, 1, 3, 6, or 12 mg/kg DTG were examined in PND 13-14 and 16-17 rats. DTG had little effect on locomotor activity on PND 13-14, although the highest dose did inhibit activity. On PND 16-17, all doses of DTG tended to increase locomotor activity. The results suggest (1) the robust locomotor effects of PCP on PND 19 are mediated in part by NMDA mechanisms (2) this period of increased sensitivity to both PCP and (+)-MK-801 might represent a critical period of development when systems mediating locomotor activity are vulnerable to neurotoxic insult (3) NMDA blockade alone does not mediate PCP-induced wall climbing behavior and (4) that at the doses of DTG and the ages tested, sigma receptors do not play a role in the locomotor-inducing effects of PCP.
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PMID:The role of NMDA and sigma systems in the behavioral effects of phencyclidine in preweanling rats. 809 Mar 59

[3H]TCP, an analog of the dissociative anesthetic phencyclidine (PCP), binds with high affinity to two sites in guinea pig brain membranes, one that is MK-801 sensitive and one that is not. The MK-801-sensitive site (PCP site 1) is associated with NMDA receptors, whereas the MK-801-insensitive site (PCP site 2) may be associated with biogenic amine transporters (BAT). Although several "BAT ligands" are known that bind selectively to PCP site 2 and not to PCP site 1 (such as indatraline), these compounds have low affinity for site 2 (Ki values > 1 microM). Here we demonstrate that the novel pyrrole RTI-4793-14 is a selective, high affinity ligand for PCP site 2. We determined the IC50 values of RTI-4793-14 and several reference compounds [PCP, (+)-MK801 and indatraline] for PCP site 1 (assayed with [3H](+)-MK801), PCP site 2 (assayed with [3H]TCP in the presence of 500 nM (+)-MK801) and a variety of BAT-related measures ([3H]CFT binding to the DA transporter, [3H]nisoxetine binding to the norepinephrine transporter, [3H]dopamine uptake, [3H]serotonin uptake). In addition, we determined the ability of RTI-4793-14 to block NMDA responses in cultured hippocampal neurons under voltage clamp. (+)-MK801 had high affinity for PCP site 1 (4.6 nM) and potently inhibited NMDA-induced responses, but was much less potent in the BAT-related measures (IC50 s > 10 microM). PCP had high affinity at PCP site 1 (IC50 = 92 nM) and PCP site 2 (IC50 = 117 nM), and was moderately potent in all BAT-related measures except [3H]nisoxetine binding.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:RTI-4793-14, a new ligand with high affinity and selectivity for the (+)-MK801-insensitive [3H]1-]1-(2-thienyl)cyclohexyl]piperidine binding site (PCP site 2) of guinea pig brain. 813 1

Phencyclidine (PCP), a psychotomimetic drug of abuse, produces mental changes and manifestations in humans which are reminiscent of schizophrenia, though the mechanism of these actions remains unknown. We report here a biphasic time course of PCP action on regional cerebral glucose metabolism extending over 48 h. A single dose of PCP (8.6 mg/kg) produces an initial increase in glucose metabolism (at 3 h) and a later decrease in glucose metabolism (at 24 h) without a return to baseline until 48 h. A single lower dose of PCP (0.86 mg/kg), a dose which is considered selective for action at the NMDA-PCP receptor, produces no early metabolic change (at 3 h), but replicates the regional hypometabolism albeit less intense at 24 h. The delayed cerebral hypometabolism does not appear to be related to PCP-induced intracellular vacuolization, seen in the retrosplenial cortex. These metabolic changes may be associated with the psychotomimetic effects of PCP and thus may be relevant to psychosis in humans.
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PMID:Delayed regional metabolic actions of phencyclidine. 822 27

The studies described demonstrate that rat brain mRNA directs the synthesis of at least four types of functional EAA receptors in the Xenopus oocyte system, whereas in this system NCB-20 cell mRNA directs the synthesis of only the NMDA type of EAA receptor. The NMDA channel expressed in the oocyte, using either rat brain mRNA or NCB-20 cell mRNA, exhibits the pharmacologic properties of the neuronal receptor, including the functional association with the PCP receptor located within the NMDA-gated channel. The demonstration that mRNA isolated from NCB-20 cells lacking functional NMDA-activated channels, but bearing PCP binding sites, can encode functional NMDA-activated channels in the oocyte indicates some defect or regulating step in posttranslational processing or insertion of the receptors into the plasma membrane in the cell of origin. This is the only cell line known to (1) have PCP receptors that appear to be associated with NMDA receptors and (2) provide a homogeneous, self-replicating population of cells that can be manipulated genetically and by changing the extracellular environment. Consequently, the NCB-20 cell line will be useful for the study of the NMDA receptor and its expression.
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PMID:Molecular biology of PCP and NMDA receptors. 823 12


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