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)

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

Ketamine and MK-801 are phencyclidine (PCP)-like noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) receptor that produce a use-dependent blockade of the NMDA receptor-coupled channel. Recent studies have suggested that the binding properties of these drugs to the NMDA receptor in-vitro are different. In the present study, the effects of ketamine and MK-801 on the induction of long-term potentiation (LTP) were compared at perforant path--granule cell synapses in anaesthetized rats. LTP was observed in animals treated with either saline or MK-801, but not in those treated with ketamine. These results reveal that ketamine and MK-801 differentially modulate the induction of LTP, and we propose that this differential modulation may be related to the different binding properties of the drugs.
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PMID:Differential effects of ketamine and MK-801 on the induction of long-term potentiation. 183 85

Electrophysiological and behavioral methods were used to evaluate and compare the effects of the competitive N-methyl-D-aspartate (NMDA) receptor blocker, NPC 12626, with the non-competitive NMDA antagonist, phencyclidine (PCP), on the activity of mesolimbic dopamine neurons. NPC 12626 (50 mg/kg, i.p.) produced a degree of locomotor hyperactivity comparable to that seen with PCP (5 mg/kg). However, 6-hydroxydopamine lesions of the nucleus accumbens blocked the PCP-induced hyperactivity but not the behavioral activation evoked by NPC 12626. Single-unit extracellular recordings from ventral tegmental A10 dopamine neurons also found marked differences between the competitive and non-competitive NMDA antagonists. Intravenous injections of NPC 12626 and CGS 19755 in doses up to 60 mg/kg failed to change A10 activity. This was in contrast to the striking bimodal dose-dependent increase-decrease in firing rate elicited by PCP. The absence of an effect of NPC 12626 on A10 neurons was not evidently related to a lack of access to central sites since NPC pretreatment (40 mg/kg, i.v.) completely antagonized the neurotoxicity caused by intrastriatal injection of quinolinic acid, an NMDA agonist, but not that caused by the non-NMDA compound, kainic acid. Thus, competitive NMDA antagonists do not share PCP's properties of activating mesolimbic dopaminergic systems, and as such they may be devoid of the potent psychotomimetic effects or the abuse liability associated with non-competitive NMDA receptor blockers such as PCP.
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PMID:Effects of competitive N-methyl-D-aspartate antagonists on midbrain dopamine neurons: an electrophysiological and behavioral comparison to phencyclidine. 183 40

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

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

The sigma receptor ligands, (+)-pentazocine and (+)-SKF 10,047, were found to increase dopamine metabolism (DOPAC, HVA) and release (3-MT) in both the striatum and olfactory tubercle of the rat, in a dose-dependent manner, after central as well as peripheral administration. The effect of (+)-SKF 10,047 was stereospecific. The increase in dopamine metabolism was not blocked by naloxone pretreatment, excluding an action via opioid receptors. More interestingly, this modulation was blocked by pretreatment with the NMDA receptor antagonist, CPP. Neither sigma ligand exhibited any affinity for D1 or D2 dopamine receptors or for NMDA, PCP or NMDA-associated glycine receptors. Sigma receptors thus appear to modulate dopaminergic function in both A9 and A10 projections. This modulation appears to involve a functional interaction with NMDA receptors or an NMDA-utilizing synapse downstream to neurons modulated by sigma receptors.
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PMID:Sigma receptors modulate both A9 and A10 dopaminergic neurons in the rat brain: functional interaction with NMDA receptors. 196 39

Both chiral forms of ketamine caused analgesia when administered in subanesthetic doses to human volunteers suffering acute, experimentally induced ischemic pain. S-Ketamine was 4 times more potent than R-ketamine as an analgesic agent in this model system. The relative order of analgesic potency of the two enantiomers was compared to their relative affinity for phencyclidine (PCP) binding sites (associated with the NMDA receptor-operated ion channel) and for sigma binding sites (which are not associated with the NMDA receptor complex). The relative analgesic potency of the enantiomers correlated positively with their relative affinity for PCP sites and negatively with their relative affinity for sigma sites. The results strongly indicate that PCP sites, but not sigma sites, are functional receptors mediating the analgesic effect of ketamine. This is consistent with the hypothesis that NMDA receptors are essential for pain perception in humans. Disturbances of other sensory modalities, in particular somatosensory perception, vision and hearing, were the main side-effects observed. These effects were qualitatively similar for both enantiomers and were closely associated with their analgesic action. The NMDA type of excitatory amino acid receptor thus appears to be widely involved in the processing of sensory afferent signals in the human brain.
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PMID:Evidence of a role for NMDA receptors in pain perception. 196 98

The electrophysiological and pharmacological properties of N-methyl-D-aspartate (NMDA)-sensitive receptors expressed in Xenopus oocytes by injection of total poly(A)+RNAs (mRNAs) from the cerebellum and cerebrum of guinea pigs were compared. The inward current induced by NMDA under voltage-clamp in cerebellar mRNA-injected oocytes was depressed in a voltage-dependent fashion by Mg2+ to show a negative slope conductance and selectively antagonized by D-2-amino-5-phosphonovalerate (D-APV) and phencyclidine (PCP). Glycine (0.01-10 microM) did not potentiate NMDA-induced currents in cerebellar mRNA-injected oocytes, while it potentiated NMDA-induced currents in cerebral mRNA-injected oocytes in a dose-dependent fashion. 6-Cyano-7-nitroquinoxaline-2,3-dione and 7-chlorokynure-nate suppressed the NMDA response but significantly less potently in cerebellar mRNA-injected oocytes than in cerebral mRNA-injected oocytes. These results suggest that the NMDA-sensitive receptor expressed in Xenopus oocytes by guinea pig cerebellar mRNA resembles the cerebral NMDA receptor in its high sensitivities to Mg2+, PCP, and D-APV, but it is distinct from the cerebral NMDA receptor in responsiveness to glycine.
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PMID:Glycine-insensitive NMDA-sensitive receptor expressed in Xenopus oocytes by guinea pig cerebellar mRNA. 197 46

The active site of minaprine (3-(2-morpholinoethylamino)-4-methyl-6-phenylpyridazine) was studied by means of receptor binding and its effect on acetylcholine (ACh) release in rat hippocampus. [3H]Minaprine binding to the hippocampal membrane was inhibited by minaprine, 4-aminopyridine (4-AP) and phencyclidine (PCP) dose-dependently, whereas it was not inhibited by L-glutamate (L-Glu), N-methyl-D-aspartate (NMDA), 2-amino-5-phosphonovalerate (APV), 3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)3-PPP) or ketamine. [3H]PCP binding was inhibited by PCP and APV in an extensively washed hippocampal membrane. Minaprine, however, failed to inhibit the [3H]PCP binding. [3H]3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) binding was inhibited by L-Glu but not by minaprine. NMDA-evoked [3H]ACh release from the rat hippocampal slices was effectively inhibited by PCP. However, minaprine had no effect on the NMDA-evoked [3H]ACh release. Similar results were obtained from the study of [3H]ACh release in the striatum. These results suggest that minaprine exerts its action via the voltage-dependent K+ channel but not via the NMDA receptor-channel complex or sigma receptor.
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PMID:Differentiation of the active site of minaprine from that of phencyclidine in rat hippocampus. 197 91

Using a two-lever operant drug discrimination paradigm, rats have been trained to discriminate between the administration of saline and R-(+)-HA-966 (R-(+)-3-amino-1-hydroxypyrrolid-2-one, 30 mg/kg i.p.) an antagonist at the glycine modulatory site on the N-methyl-D-aspartate (NMDA) receptor/ion channel complex. Drug-appropriate responding was not induced in stimulus generalisation experiments when the non-competitive NMDA receptor antagonist, phencyclidine (PCP, 1-8 mg/kg i.p.) was substituted for (+)-HA-966. Similarly, (+)-HA-966 (6-50 mg/kg i.p.) did not induce drug-appropriate responding in animals trained to discriminate PCP (3 mg/kg i.p.) from saline. The results suggest that the behavioural profile of compounds attenuating the actions of NMDA via blockade of the glycine modulatory site may be substantially different from those acting at the ion channel of the NMDA receptor complex.
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PMID:The discriminative stimulus properties of (+)-HA-966, an antagonist at the glycine/N-methyl-D-aspartate receptor. 214 38


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