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 examined the behavioural effects of sigma agonists and PCP-like non-competitive N-methyl-D-aspartate (NMDA) antagonists in guinea-pigs. Subcutaneous (SC) injection of the putative sigma agonist (+)NANM (1 and 10 mg/kg SC) and (-)NANM (1 and 10 mg/kg SC) produced a behavioural response in guinea-pigs which was characterized by sedation and exophthalmos, with locomotor depression, flattened posture and flaccidity, whereas the sigma ligand pentazocine induced sedation but no flattened posture. Ketamine (20 mg/kg SC) and (+)dizocilpine (0.025, 0.1 and 1 mg/kg SC) produced similar effects to those of (+) and (-)NANM. However, the putative sigma receptor ligand DTG (1 and 10 mg/kg SC) had no observable effect on behaviours in guinea-pigs, similar to results for other species. The behavioural effects produced by (+) and (-)NANM were not reversed by injection 1 h later of naloxone hydrochloride (15 mg/kg SC), haloperidol (10 mg/kg SC) or DTG (10 and 30 mg/kg SC), but the effects of all drugs were reversed by the selective dopamine D-2 agonist quinpirole (3 mg/kg IP). Moreover, injection of naloxone (15 mg/kg SC), DTG (10 and 30 mg/kg SC) or haloperidol (1 and 10 mg/kg SC) 10 min before, did not reverse the behaviour induced by (+)NANM (10 mg/kg SC). These data indicate that sigma and PCP-like drugs have a similar gross behavioural effect in guinea-pigs, possibly mediated by non-competitive antagonism of the NMDA subtype of glutamate receptors. The results demonstrating behavioural depression were in contrast to the stimulatory effects of these drugs at similar doses in other rodent species.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Similar behavioural effects of sigma agonists and PCP-like non-competitive NMDA antagonists in guinea-pigs. 168 18

Polyamines such as spermidine potentiate activation of the N-methyl-D-aspartate (NMDA)-type excitatory amino acid receptor. The goal of the present study was to investigate interactions between the putative polyamine binding site and previously described sites for glutamate and glycine. Binding of the high-potency PCP receptor ligand [3H]MK-801 to well-washed rat brain membranes was used as an in vitro probe of NMDA receptor activation. Spermidine concentration-response studies were performed in the absence and presence of both glutamate and glycine, with and without D-(-)-2-amino-5-phosphonovaleric acid (D(-)-AP-5) or 7-chlorokynurenic acid (7Cl-KYN). Incubation in the presence of spermidine alone induced a 20.4-fold increase in [3H]MK-801 binding with an EC50 value of 13.3 microM. The mean concentration of spermidine which induced maximal stimulation of binding was 130 microM (n = 10, S.E.M. = 24.66, range = 25-250 microM). Glutamate (10 microM) decreased the EC50 value for spermidine-induced stimulation of [3H]MK-801 binding to 3.4 microM. Glycine (10 microM) did not significantly alter either maximum spermidine-induced [3H]MK-801 binding or the EC50 value for spermidine-induced stimulation of [3H]MK-801 binding. Incubation in the presence of the specific glutamate antagonist D(-)AP-5 attenuated [3H]MK-801 binding in a glutamate-reversible fashion. The competitive glycine antagonist 7Cl-KYN decreased maximum spermidine-induced [3H]MK-801 binding in a glycine-reversible fashion. In addition, 7Cl-KYN increased the EC50 value for spermidine-induced stimulation of [3H]MK-801 binding while D(-)AP-5 was without effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Polyamine effects upon N-methyl-D-aspartate receptor functioning: differential alteration by glutamate and glycine site antagonists. 168 87

The phencyclidine (PCP) binding site of the N-methyl-D-aspartate receptor, the kainic acid (KA) receptor and the quisqualate (QA) receptor were visualised, using autoradiography in the human spinal cord and the distributions compared with that of benzodiazepine (BDZ) receptors and substance P (SP). All of the receptor types, and SP, were concentrated in lamina II of the dorsal horn, consistent with physiological data indicating that glutamate is a neurotransmitter of primary afferent terminals in the spinal cord.
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PMID:Autoradiographic localisation of NMDA, quisqualate and kainic acid receptors in human spinal cord. 168 76

Because of its apparent effectiveness in detecting non-benzodiazepine anxiolytic agents, a recently introduced conflict procedure in pigeons was used to evaluate possible anti-punishment activity of various N-methyl-d-aspartate (NMDA) antagonists. Punished responding was significantly increased by competitive NMDA antagonists (CPP, CGS 19755), but not by noncompetitive NMDA antagonists acting at either the ion channel (PCP, ketamine, MK-801), the glycine site (kynurenic acid, 7-chlorokynurenic acid, ACPC), or the polyamine site (ifenprodil) of the NMDA receptor complex; the proposed glutamate antagonist, riluzole, was also ineffective.
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PMID:Use of a conflict procedure in pigeons to characterize anxiolytic drug activity: evaluation of N-methyl-D-aspartate antagonists. 171 31

Drugs (e.g., PCP) which interfere with glutamatergic transmission at the N-methyl D-aspartate (NMDA) subclass of glutamate receptors precipitate both positive and negative symptoms of psychosis in humans. Based on a proposed "glutamatergic deficiency" in schizophrenia, pharmacologic facilitation of NMDA-mediated neural transmission by direct stimulation of the strychine-insensitive glycine binding site was attempted with "low-dose" milacemide, an acylated "prodrug" of glycine that readily crosses the blood brain barrier and is converted into glycine in the brain. In a prior study, "high-dose" milacemide proved to have no therapeutic utility in schizophrenia. The failure was thought, possibly, to be related to higher doses of milacemide having antagonist actions at the NMDA receptor complex. In the current study, "low-dose" milacemide (400 mg/day), as the sole pharmacotherapeutic agent, was also without significant clinical benefit. Despite our negative findings for milacemide, other strategies for facilitating NMDA-mediated neural transmission in schizophrenia might be worth pursuing.
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PMID:An NMDA intervention strategy in schizophrenia with "low-dose" milacemide. 153 74

Derivatives with fluoromethyl and hydroxymethyl groups on the cyclohexyl ring of 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP), a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptor, were tested in a radioligand binding assay to evaluate their ability to inhibit [3H]TCP binding by rat brain homogenates. The potencies of these compounds as antagonists of NMDA and L-glutamate responses were also compared using a rat cortical slice preparation. One of the analogs, cis-2-hydroxymethyl-r-1-(N-piperidyl)-1-(2-thienyl) cyclohexane (5) was found to show a high affinity (IC50 = 16 nM) for the phencyclidine (PCP) binding sites, very close to that of TCP, and to be 38-fold more potent in binding than its trans isomer. Fluoromethyl and hydroxymethyl substitutions at C4 position of the cyclohexyl ring of TCP clearly reduced the affinity by at least one order of magnitude relative to TCP.
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PMID:Fluoromethylated and hydroxymethylated derivatives of N-methyl-D-aspartate receptor antagonist 1-[1-(2-thienyl)cyclohexyl]piperidine. 183 57

Based on results from the kindling model of epilepsy, we hypothesized that enhanced binding of radioligands to the NMDA receptor and decreased binding to the alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionate (AMPA)-sensitive quisqualate (ASQ) receptor would be found within epileptic hippocampi of humans with complex partial epilepsy (CPE). To test these hypotheses, we used tissue that was surgically removed from patients with intractable CPE, and control tissue that was obtained at autopsy. We used autoradiographic techniques to measure ASQ receptor binding (with 3H-AMPA as the radioligand) and binding to 2 sites on the NMDA receptor/channel complex: the agonist recognition site (with 3H-glutamate) and the phencyclidine (PCP) binding site that resides within the NMDA channel [with 3H-N-(1-[thienyl]cyclohexyl) piperidine (TCP) in the presence of saturating concentrations of NMDA and glycine]. Measurements of receptor binding were corrected for pathologic alterations in neuronal density. Contrary to our expectations, ASQ receptor binding was significantly increased (100%; p less than 0.02) in the dentate gyrus stratum moleculare in patients with CPE (n = 8), and it was unchanged in other hippocampal regions. In nearby sections from the same specimens, binding was significantly decreased to the agonist recognition site of the NMDA receptor in the stratum oriens of area CA3 (46%; p less than 0.05) and was also decreased to the PCP site in the stratum radiatum and stratum oriens of CA3 (44% and 74%, respectively; p less than 0.05). The increase in ASQ receptor binding may contribute to hyperexcitability in these epileptic patients.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Increased AMPA-sensitive quisqualate receptor binding and reduced NMDA receptor binding in epileptic human hippocampus. 184 7

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

The neuronal localization of glutamate and phencyclidine (PCP) receptors was evaluated in the cerebral cortex and hippocampal formation of rat CNS using quantitative autoradiography. Scatchard analysis of [3H]glutamate binding in the cortex (layers I and II and V and VI) showed no difference in the total number of binding sites (Bmax) or apparent affinity (Kd) 1 week, 1 month and 2 months following unilateral ibotenate lesions to nucleus basalis of Meynert (nbM) compared to the non-lesioned side. Quisqualic acid displacement of [3H]glutamate in layers I and II, 1 week following nbM destruction, revealed both high- and low-affinity binding sites (representing the quisqualate (QA) and N-methyl-D-aspartate (NMDA) sites, respectively). Compared to the control side, there was no difference in binding parameters for either of the receptor sites. In similarly lesioned animals, the NMDA receptor was specifically labelled with [3H]glutamate and the associated PCP receptor labelled with [3H]N-(1-[2-thienyl]cyclohexyl)3,4-piperidine ([3H]TCP) in adjacent brain sections. For both receptors, there was no change in the total number of binding sites in the cortex following destruction of nbM. On the other hand, virtually all binding to NMDA and PCP receptors was eliminated following chemical destruction of intrinsic cortical neurons. These results suggest that the NMDA/PCP receptor complex does not exist on the terminals of cortical cholinergic afferents. One week after knife cuts of the glutamatergic entorhinal pathway to the hippocampal formation only an approximate 10% reduction of NMDA and PCP receptors was seen in the dentate gyrus. Conversely, selective destruction of the dentate granule cells using colchicine caused a near identical loss of NMDA and PCP receptors (84% vs 92% respectively). It is concluded from these experiments that glutamate and PCP receptors exist almost exclusively on neurons intrinsic to the hippocampal formation and that no more than 10% of NMDA and PCP receptors exist as autoreceptors on glutamatergic terminals.
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PMID:A study of cortical and hippocampal NMDA and PCP receptors following selective cortical and subcortical lesions. 185 Mar 17

Recently, the presence of two high affinity binding sites for phencyclidine were described in guinea pig brain, with one site coupled to the glutamate excitatory amino acid receptor, specifically activated by N-methyl-D-aspartate (NMDA) (site 1) and the other site associated with the dopamine (DA) reuptake carrier (site 2). Phencyclidine and its analogs, as well as the benzomorphan opiates, are known to interact with binding sites for phencyclidine. In this study, the equilibrium dissociation constants (Kd) of these compounds for the two binding sites for phencyclidine were determined. Phencyclidine and 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP), an analog of PCP, were essentially non-selective between the two sites and also were the two drugs of the group observed to have the highest affinity for site 2. (+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5,10-imine [(+)MK801] was the most selective agent for site 1, while none of the drugs tested showed selectivity for site 2. In humans, phencyclidine produces psychotomimetic effects, while (+)MK801 has been reported to produce minimal, if any, psychotomimetic effects, at doses sufficient to reduce seizures. These clinical observations, in conjunction with the present biochemical binding data, suggest that (+)MK801 may serve as a "marker" for site 1 and that the psychotomimetic effects of phencyclidine might be mediated by site 2.
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PMID:Specificity of phencyclidine-like drugs and benzomorphan opiates for two high affinity phencyclidine binding sites in guinea pig brain. 196 80


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