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)

Neurochemical interactions of tiletamine, a potent phencyclidine (PCP) receptor ligand, with the N-methyl-D-aspartate (NMDA)-coupled and -uncoupled PCP recognition sites were examined. Tiletamine potently displaced the binding of [3H]1-(2-thienyl)cyclohexylpiperidine with an IC50 of 79 nM without affecting sigma-, glycine, glutamate, kainate, quisqualate, or dopamine (DA) receptors. Like other PCP ligands acting via the NMDA-coupled PCP recognition sites, tiletamine decreased basal, harmaline-, and D-serine-mediated increases in cyclic cGMP levels and induced stereotypy and ataxia. Tiletamine was nearly five times more potent than PCP at inhibiting the binding of 3-hydroxy[3H]PCP to its high-affinity NMDA-uncoupled PCP recognition sites. However, following parenteral administration, dizocilpine maleate (MK-801), ketamine, PCP, dexoxadrol, and 1-(2-thienyl)cyclohexylpiperidine HCl, but not tiletamine, increased rat pyriform cortical DA metabolism and/or release, a response modulated by the NMDA-uncoupled PCP recognition sites. Pretreatment with tiletamine did not attenuate the MK-801-induced increases in rat pyriform cortical DA metabolism, a result suggesting that tiletamine is not a partial agonist of the NMDA-uncoupled PCP recognition sites in this region. However, following intracerebroventricular administration (100-500 micrograms/rat), tiletamine increased pyriform cortical DA metabolism with a bell-shaped dose-response curve. These data indicate a differential interaction of tiletamine with the NMDA-coupled and -uncoupled PCP recognition sites. The paradoxical effects of tiletamine suggest that tiletamine might activate receptor(s) or neuronal pathways of unknown pharmacology.
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PMID:Contrasting neurochemical interactions of tiletamine, a potent phencyclidine (PCP) receptor ligand, with the N-methyl-D-aspartate-coupled and -uncoupled PCP recognition sites. 184 86

D-Serine, a selective agonist at the strychnine-insensitive glycine binding site, antagonized PCP-induction of stereotyped behavior and ataxia in a dose-dependent manner. At intraventricular doses of 0.1, 0.5 and 1 mumol/rat, D-serine significantly attenuated PCP-induction of stereotyped behavior in rats. Only doses of 0.5 and 1.0 mumol/rat of D-serine antagonized PCP-induction of ataxia. D-Serine (0.5 mumol/rat) also antagonized MK-801 induced stereotyped behavior and ataxia. These results suggest that agonists at the strychnine-insensitive glycine site may be clinically useful as a novel class of atypical antipsychotic agents.
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PMID:D-serine antagonized phencyclidine- and MK-801-induced stereotyped behavior and ataxia. 210 76

We have investigated whether metaphit, a derivative of phencyclidine (PCP) which irreversibly binds to a population of PCP receptor sites in rat brain, blocks PCP-induced head-twitch response which is produced through serotonin2 (5-HT2) receptors, and also whether metaphit decreases the capacity of 5-HT2 receptors. Metaphit (1 mumol/rat) had decreased the intensity of PCP-induced head-twitch response and had depleted both PCP and 5-HT2 receptors by 24 h after administration, but it failed to block 5-HT agonist 5-methoxy-N,N-dimethyltryptamine-induced 5-HT1A receptor-dependent behaviors. These results reconfirmed our hypothesis that PCP and 5-HT2 receptors may have very similar binding sites.
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PMID:Effects of metaphit on phencyclidine and serotonin2 receptors. 255 11

The acute administration of phencyclidine (PCP) causes hypothermia in the rat. Metaphit (1-[1-(3-isothiocyanatophenyl)cyclohexyl]-piperidine) is a derivative of PCP that has been shown to irreversibly acylate PCP receptors in vitro and in vivo and can antagonize the behavioral and electrophysiological effects of PCP in the rat. The purpose of the present study was to determine whether pretreatment with metaphit can block the hypothermic effects of PCP in the rat. Metaphit or PCP (1.0 mumol/rat) were injected into the lateral ventricles of rats, and 24 hr later the subjects were challenged with PCP (20.0 mg/kg s.c.). Pretreatment with metaphit blocked PCP-induced hypothermia; however, pretreatment with PCP did not affect the subsequent hypothermic response to PCP. These results indicate that the antagonism of PCP-induced hypothermia by metaphit was a specific effect and not due to PCP receptor desensitization.
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PMID:Metaphit antagonizes phencyclidine-induced hypothermia in the rat. 277 Apr 9

Metaphit, which acylates phencyclidine (PCP) receptors in vitro, was shown to acylate PCP receptors and antagonize the behavioral and electrophysiological effects of PCP in vivo. Metaphit (2 mumol/rat) administered i.c.v. produced PCP-like stereotyped behavior and ataxia in 10 to 20% of rats. At a lower dose, Metaphit (1 mumol/rat) antagonized the ability of PCP to induce stereotyped behavior and ataxia for 3 and 4 days, respectively. The Metaphit-induced antagonism of PCP induction of stereotyped behavior and ataxia was dose-dependent and specific as Metaphit did not antagonize induction of stereotyped behavior by amphetamine. Further evidence for a specific PCP receptor mechanism was the finding that PCP pretreatment blocked the effects of subsequent Metaphit administration. Metaphit also antagonized PCP-induction of stereotyped behavior, but not ataxia, after i.v. administration. Doses of Metaphit that produced long-term antagonism of the behavioral effects of PCP also produced a significant decrease in the maximum binding, but not Kd, of the binding of the PCP analog, [3H]-1-(2-thienyl)cyclohexyl]piperidine, in Metaphit-pretreated rats. The binding of [3H]etorphine and [3H]spiroperidol was not altered significantly by pretreating rats with Metaphit. (-)-Cyclazocine and (+)-SKF 10,047 induced stereotyped behavior and ataxia that was not antagonized by Metaphit-pretreatment. In electrophysiological experiments, Metaphit, like PCP, initially depressed the firing of caudate neurons as does PCP, but then irreversibly inhibited PCP-induced depression of caudate neurons. These results suggest that metaphit antagonized the effects of PCP by selectively acylating PCP receptors and that (-)-cyclazocine- and (+)-SKF 10,047-induced behavioral effects are not mediated primarily by PCP receptors.
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PMID:Metaphit, an acylating ligand for phencyclidine receptors: characterization of in vivo actions in the rat. 301 19

Male rats were injected with 3H-PCP (3 mg/kg; 1.2 mCi/rat) into the tail vein. Three minutes later, the rats were anesthetized, frozen and their heads processed for autoradiographic study. The autoradiograms illustrated diffuse distribution of 3H-PCP or its metabolites in the whole brain tissue. Increased intensity was observed in the hippocampus, corpus callosum, subicullum, thalamus, colliculus caudalis, nucleus caudatus putamen, hypothalamus, and cerebellum. These labelled regions are in accord with those which were found to change glucose metabolism, as has been observed by monitoring labelled deoxyglucose before and after PCP injection. In addition to the previously mentioned sites, radioactivity is seen in the olfactory bulb, chiasma opticus and parts of the eye (lens cortex, retina, cilliary body). The presence of radioactivity in the chiasma opticus, as well as in various parts of the eye itself, may partially explain the effect of PCP on the eye and on vision.
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PMID:Localization of phencyclidine in the rat brain in vivo. 657 11

The central distribution of sigma sites labelled by di-o-tolylguanidine (DTG), a compound which has specific affinity for sigma sites, and its ability to produce postural movements, are consistent with the hypothesis that sigma sites may play a functional role in the regulation of movement. The aim of the present study was to evaluate the specificity of the circling behaviour induced by unilateral intranigral injection of DTG in rats. As previously described, DTG produced dose-dependent unilateral rotations (2.5-20 nmol/rat). A similar dose-dependent circling behaviour was observed with DMTG and (+) NANM (3-40 nmol/rat), compounds which bind to both sigma and PCP sites, and with haloperidol (3-20 nmol/rat) whereas raclopride and D,L-sulpiride did not elicit any circling (10 nmol/rat). DTG-induced circling after intranigral injection (10 nmol/rat) was decreased in a dose-dependent manner by rimcazole (20-40 mg/kg, i.p.), a selective ligand for sigma sites, and by BMY 14802 (3, 10, 30 mg/kg, i.p.), ifenprodil and eliprodil (1, 3, 10 mg/kg, i.p.), non-selective sigma ligands. In contrast, naloxone (1 mg/kg, s.c.) and CGS 19755 (1, 3, 10 mg/kg, i.p.) did not change the DTG-induced circling. Eliprodil failed to inhibit circling produced by compounds devoid of any affinity for sigma sites such as APV, dizocilpine or muscimol, indicating the specificity of the inhibition observed with eliprodil on the DTG-induced circling.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacological evidence for the involvement of sigma sites in DTG-induced contralateral circling in rats. 762 59

Intracerebroventricular injection of the D-forms of alanine (Ala; 2-200 micrograms/rat) and serine (Ser; 20-2000 micrograms/rat) caused a dose-dependent inhibition of the ability of 10 mg/kg of phencyclidine (PCP; given i.p.) to increase automatically quantitated locomotor counts and cumulated scores of locomotion, stereotypy and ataxia for 90 min after PCP administration. D-Ala and D-Ser were found to be more potent than the corresponding L-isomers in attenuating the PCP-induction of these behavioral abnormalities. Although L-, but not D-Ser, at moderate doses (400 micrograms/rat) produced a slight decrease in cumulative ataxia scores after a 10-mg/kg PCP administration, D-, but not L-Ser, reduced the behavioral scores at large doses (more than 1000 micrograms/rat). Similarly, bilateral i.c.v. infusion of D-Ala (140 micrograms/rat) reduced the increasing effects of a lower dose of PCP (5 mg/kg i.p.) on locomotion, stereotypy and ataxia scores, whereas the L-form of Ala (140 micrograms/rat) lacked the inhibitory influence. The stereo-selectivity of the antagonism by Ala and Ser of PCP-induced abnormal behavior parallels that of the potencies of these amino acids as agonists for the strychnine-insensitive glycine site linked to the N-methyl-D-aspartate type excitatory amino acid receptor. Furthermore, the decreasing effects of D-Ala (200 micrograms/rat i.c.v.) and D-Ser (2000 micrograms/rat i.c.v.) on PCP-induced hyperactivity were antagonized by i.c.v. application of 5,7-dichlorokynurenate and 7-chlorokynurenate which are selective antagonists of the glycine modulatory site.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Stereoselective antagonism by enantiomers of alanine and serine of phencyclidine-induced hyperactivity, stereotypy and ataxia in the rat. 801 48

Amantadine (1-amino-adamantane) is clinically used for the management of Parkinson's disease and drug-induced extrapyramidal symptoms. It has previously been shown that amantadine is a low-affinity uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist with rapid blocking and unblocking channel kinetics (Ki-value at the PCP binding site = 10 microM). The aim of the present studies was to estimate concentrations of amantadine in the central nervous system under therapeutic conditions. In homogenates of postmortem human brain tissue the amantadine concentration appeared to be homogeneously distributed over a wide range of brain areas. Amantadine concentration increased with duration of treatment and decreased wit drug-free time. When the duration of treatment was > or = 10 days and drug-free time < or = 3 days, mean amantadine concentrations in postmortem brain tissue ranged from 48.2 to 386 microM. In contrast to brain tissue, amantadine concentration in cerebrospinal fluid (CSF) and serum was in the low micromolar range ( < 17 microM). CSF and serum total values were highly correlated to each other and were always lower in CSF. The mean CSF/serum ratio for total amantadine was 0.76. To further estimate the extracellular concentration, amantadine was determined in microdialysates in the rat striatum. At behaviorally active doses, amantadine concentration in striatal microdialysates ranged between 6 and 21 microM. These results indicate that extracellular concentrations of amantadine (CSF and serum values in patients, striatal microdialysates in the rat) are in the range of its Ki-value at the PCP binding site. Amantadine concentrations in brain tissue are much higher, probably due to intralysosomal accumulation.
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PMID:Therapeutic brain concentration of the NMDA receptor antagonist amantadine. 853 38

Previous studies have shown that social withdrawal in the phencyclidine (PCP) rat model of schizophrenia results from deficient endocannabinoid-induced activation of CB1 receptors. To understand the underlying cognitive mechanisms of the social deficit in PCP-treated rats, we examined the impact of pharmacological manipulation of the endocannabinoid system on sociability (i.e. social approach) and social novelty preference (which relies on social recognition). Control rats showed a clear preference for a "social" cage (i.e. unfamiliar stimulus rat placed under a wire mesh cage) versus an "empty" cage, and spent more time exploring a "novel" cage (i.e. new stimulus rat) versus a "familiar" cage. In contrast, rats receiving PCP (5 mg/kg, b.i.d. for 7 days, followed by a 7 day-washout period) showed intact sociability, but lacked social novelty preference. This PCP-induced deficit was due to increased activity at CB1 receptors as it was reversed by systemic administration of the CB1 antagonist AM251 (1 mg/kg). In agreement with this hypothesis, the cannabinoid agonist CP55,940 (0.003-0.03 mg/kg) dose-dependently suppressed social novelty preference in control animals without affecting sociability. Taken together, these data suggest that PCP-treated rats have a deficit in social cognition, possibly induced by increased stimulation of CB1 receptors. This deficit, however, is distinct from the social withdrawal previously observed in these animals, as the latter is due to deficient, rather than increased, CB1 stimulation.
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PMID:Disruption of social cognition in the sub-chronic PCP rat model of schizophrenia: Possible involvement of the endocannabinoid system. 2670 91


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