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 effects of the calcium channel blocker nimodipine and the non-competitive NMDA-antagonists MK-801 and phencyclidine (PCP) on infarct size 48 h after occlusion of the middle cerebral artery (MCA-O) were evaluated in the rat. Nimodipine was given at a dose of 0.3 mg/kg s.c. 30 min prior and 8, 16, and 24 h after MCA-O. MK-801 (1 mg/kg i.p. or 10 mg/kg i.p.) or PCP (0.3, 1.0, 3.0, 10, or 30 mg/kg i.p.) were administered 30 min prior to ischemia. In additional experiments 30 mg/kg PCP was given 1, 3, or 5 h post ischemia. Nimodipine and 1 mg/kg MK-801 reduced cortical infarct volumes significantly by 50% and 55%, respectively, while cortical infarct size fell by 32% and total infarct volume was not altered significantly after administration of 10 mg/kg MK-801. Pretreatment with 10 or 30 mg/kg PCP reduced cortical infarction by 47-53% and total infarct volumes by 39-42%. Posttreatment with PCP was effective if started at 1 or 3 h post ischemia.
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PMID:The effects of dizocilpine (MK-801), phencyclidine, and nimodipine on infarct size 48 h after middle cerebral artery occlusion in the rat. 191 95

Nicardipine and other calcium channel effectors (CCEs) were studied for their effects on nicotinic acetylcholine receptor (nAChR) activity. While CCEs had no effect on frog (Rana pipiens) skeletal muscle contractions resulting from nerve stimulation or direct stimulation of the muscle, nicotinic agonist-induced contractures were blocked. Nicardipine did not affect nAChR single-channel open time or amplitude, corroborating data from endplate currents (EPCs); EPC amplitudes and decays were unaffected. All the CCEs tested, however, non-competitively blocked nAChRs. The block of nAChRs resulted in a shortened agonist-induced depolarization and thus a diminished contracture response. An increase in cultured mouse skeletal muscle (C-2) cell single-channel closed times was observed with the intracellular addition of nicardipine, verifying a direct block of nAChRs. Using single-channel analysis, nicardipine's site of action, or at least access to its site of action, was determined to be at the intracellular side of the receptor. A direct action of the CCEs on the nAChR was also shown by their ability to block phencyclidine (PCP) binding to Torpedo nobiliana membranes. All the CCEs blocked specific binding of [3H]-PCP to its binding site on the nAChR-channel complex, with bepridil and nicardipine being the most potent. These data are compatible with a model in which nicardipine and other CCEs, at concentrations which do not alter nAChR channel open time or conductance, block the effects of superfused nicotinic agonist on nAChRs either by stabilizing the formation of the nAChR desensitized state or by effecting a slow channel block.
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PMID:Calcium channel effectors are potent non-competitive blockers of acetylcholine receptors. 217 19

Phencyclidine (PCP) significantly reduces the apparent dissociation constant (KD) of the dihydropyridine (DHP) calcium channel antagonist, [3H]nitrendipine, in synaptosomal membranes of rat and mouse brain without significantly effecting the maximum binding capacity (Bmax). At an optimum concentration of PCP (10 microM) the apparent KD of [3H]nitrendipine was reduced from 178 +/- 9 pM to 112 +/- 9 pM in rat forebrain, a 58% increase in affinity. The structural derivatives of PCP, P-Br-PCP [1-[1-(4-bromo-phenyl-cyclohexyl)piperidine]], m-NH2-PCP [1-[1-(3-anilo)-cyclohexyl]piperidine], (+/-)-PCMP [1-(1-phenyl)-cyclo-hexyl-3-methylpiperidine] also increased the apparent affinity of [3H]nitrendipine in the following order, p-Br-PCP much greater than PCMP greater than PCP greater than m-NH2-PCP. Local anesthetics either reduced the apparent affinity of [3H]nitrendipine or had no effect. Kinetic analysis revealed that PCP both increased the microassociation rate constant and decreased the microdissociation rate constant of [3H]nitrendipine. The magnitude of this enhanced binding varied with the brain region studied; the greatest increase in apparent affinity of [3H]nitrendipine was observed in striatum, while no significant increase in affinity was observed in brainstem. In some brain areas, PCP was more effective in reducing the KD in crude homogenates than in washed tissue. PCP (10 microM) did not alter the KD of [3H]nitrendipine to rat cardiac tissue. Both Ca2+ and Mg2+ inhibited the effect of PCP, while monovalent ions were ineffective in this regard.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phencyclidine increases the affinity of dihydropyridine calcium channel antagonist binding in rat brain. 293 50

The abilities of compounds structurally or pharmacologically related to phencyclidine to increase the apparent affinity of the [3H]dihydropyridine calcium channel antagonist [3H]nitrendipine were examined in lysed synaptosomal membrane preparations of rat brain. The p-bromo analog of phencyclidine (1-(1-(4-bromophenyl)cyclohexyl)piperidine) was the most efficacious compound tested in enhancing the apparent affinity of [3H]nitrendipine. The efficacy of this compound was approximately two-fold greater than PCP. The stereoisomers of PCMP (1-(1-phenylcyclohexyl-3-methylpiperidine) were also more efficacious than phencyclidine, although only a small degree of stereoselectivity was observed. Levoxadrol, dexoxadrol and the enantiomers of ketamine did not potentiate [3H]nitrendipine binding. The enantiomers of SKF 10047 (n-allylormetazocine), dextrorphan, levorphanol and the ion channel toxins histrionicotoxin and pumiliotoxin-B also increased the apparent affinity of [3H]nitrendipine, while several local anesthetics and mu-opiate receptor ligands were without effect. These studies suggest that the ability of phencyclidine and structurally related compounds to increase the apparent affinity of [3H]nitrendipine is not mediated through an interaction with phencyclidine receptors, but may represent a unique site for allosteric modulation of neuronal dihydropyridine calcium channel antagonist binding sites.
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PMID:Enhancement of brain calcium antagonist binding by phencyclidine and related compounds. 293 63

An autoradiographic analysis of high-affinity binding sites for the vesicular acetylcholine transport blocker [3H]vesamicol (2-(4-phenylpiperidino) cyclohexanol; AH 5183) was conducted in rat brain. [3H]Vesamicol binding was displaced 52-99% by DPPN [( 2,3,4,8]-decahydro-3-(4-phenyl-1-piperidinyl)-2-napthalenol) (IC50 = 14 nM) and by ketanserin (500 nM), haloperidol (43 nM), and vesamicol analogs, but not by drugs selective for adenosine, adrenergic, amino acid, calcium channel, monoaminergic, opioid, PCP, sigma, or several other receptor classes. [3H]Vesamicol binding was most concentrated in the interpeduncular nucleus and fifth and seventh cranial nerve nuclei. Moderate binding was found in the lateral caudate-putamen, medial nucleus accumbens, olfactory tubercle, vertical and horizontal diagonal bands of Broca, and basolateral amygdala. The distribution of [3H]vesamicol binding was similar to distributions of acetylcholine (r = 0.88), acetylcholine esterase (r = 0.97), choline acetyltransferase (ChAT) (r = 0.97), and [3H]hemicholinium-3 binding sites (r = 0.95-0.99). Lower correlations were obtained between [3H]vesamicol and muscarinic receptor densities (r = 0.50-0.70). Few exceptions to the match between binding and cholinergic neuronal markers were found, e.g., the molecular layer of the cerebellum and the thalamus. Lesions of cholinergic neuronal projections to the neocortex or hippocampus reduced [3H]vesamicol binding in each of these regions, but to a lesser extent than reductions in ChAT. [3H]Vesamicol binding sites appear to be anatomically associated with brain cholinergic neurons, a locus that is consistent with the control by this site of vesicular acetylcholine uptake.
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PMID:[3H]vesamicol binding in brain: autoradiographic distribution, pharmacology, and effects of cholinergic lesions. 297 45

Sixteen calcium channel inhibitors (CCI's) were tested in a model utilizing phencyclidine (PCP)-induced behavioral stimulation in mice. There were marked differences in the effects of CCI's both within subclasses and between subclasses of CCI's. All of the dihydropyridines and possibly flunarizine were effective in blocking PCP-induced behavioral stimulation. Papaverine derivatives, including verapamil, and several other CCI's, were ineffective.
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PMID:Differences between calcium channel inhibitors in their effects on phencyclidine-induced behavioral stimulation in mice. 407 Mar 37

Although barbiturates are often effective as therapeutic agents in several types of brain ischemia, there is no consensus as to their mechanisms of action. Exactly why other intravenous anesthetics such as ketamine are not effective therapies in brain ischemia is not known. Structural analogs of ketamine such as phencyclidine (PCP) not only exert potent hallucinogenic properties and are widely abused drugs, but often result in hypertensive encephalopathies and death. In view of the paucity of information on the cerebral circulatory actions of barbiturates, ketamine and PCP (and analogs), in-vivo (microcirculatory) and in-vitro studies were undertaken. Barbiturates, in anesthetic concentrations (e.g., 10(-5) to 10(-4) M), were found to exert direct vasodilator actions on cerebral arterial smooth muscle; these relaxant actions appear to be related to inhibition of calcium ion (Ca2+) influx in cerebral vessels. The latter may be important in the salutory actions of barbiturates in brain ischemia, head trauma and cerebrovasospasm. Unlike barbiturates, ketamine was found to exert spasmogenic actions on cerebral arteries, which may aid in explaining the inability of this anesthetic to be of therapeutic value in brain ischemia. PCP and its analogs, as well as other hallucinogenic molecules (e.g., LSD, mescaline) produced spasms in cerebral arterioles, venules and arteries in concentrations which mimic their hallucinogenic potencies. Distinct PCP-like receptors which subserve contraction appear to exist on large as well as microscopic cerebral blood vessels. Spasms induced by PCP, its analogs and ketamine can be readily reversed or prevented completely by calcium channel blockers. The latter agents could be quite useful, clinically, in prevention of cerebral infarction, hypertension and fatality associated with PCP (and analogs) intoxication.
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PMID:Effects of barbiturates, phencyclidine, ketamine and analogs on cerebral circulation and cerebrovascular muscle. 640 Apr 29

Phencyclidine (PCP) and ketamine are known to block NMDA receptor mediated excitotoxicity by non-competitively blocking the NMDA receptor calcium channel. PCP and ketamine have the paradoxical effect of also inducing the heat shock gene, hsp70, in the cingulate and retrosplenial cortex of the rat. The present study shows that DNQX, a specific AMPA receptor antagonist, given as either a 5 mg/kg or 10 mg/kg intraperitoneal dose or into the lateral cerebral ventricle (5 microliters of 0.5 mg/ml) significantly diminished PCP (40 mg/kg) and ketamine (80, 100, 120 mg/kg) hsp70 induction in the posterior cingulate and retrosplenial cortex. The most dramatic decrease of hsp70 induction was seen with the intraventricular dose of DNQX. Present findings show that the AMPA receptor has a role in PCP/ketamine induction of hsp70 in the cortex. DNQX inhibition of PCP/ketamine hsp70 induction was likely related to AMPA receptor antagonism which prevented excess calcium influx via voltage-gated calcium channels.
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PMID:DNQX inhibits phencyclidine (PCP) and ketamine induction of the hsp70 heat shock gene in the rat cingulate and retrosplenial cortex. 758 95

Omega-conotoxin (1 and 2 micrograms/10 microliter i.c.v.), a N-type calcium channel blocker, and amiloride (7.5 and 15 micrograms/10 microliter i.c.v.), a T-type calcium antagonist, significantly prevented the EEG and behavioural effects induced by phencyclidine (PCP, 5 mg/kg i.p.) in rats. In accordance with previous studies showing the significant influence of L-type calcium blockers in the same model, these results confirm that the modulation of calcium currents plays a key role in the expression of PCP-induced effects.
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PMID:Influence of non-L-type calcium channel antagonists on phencyclidine-induced effects in rats. 850 32

The physiological model for glutamate receptor mediated excitotoxicity entails elevation of intraneuronal calcium levels. Excessive activation of the NMDA receptor leads to excitotoxicity by prolonged calcium influx via its calcium channel. The purpose of this research was to examine the mechanism of non-NMDA glutamate receptor mediated excitotoxicity. Mammalian AMPA receptors do not show significant calcium conductance. However, some kainate receptors show significant calcium conductance. The hypothesis of this research states that non-NMDA glutamate agonists (quisqualate (5 microliters of 2 mg/ml i.c.v.), AMPA (4 microliters of 1 mg/ml i.c.v.), and kainate (15 mg/kg i.p.)) produce significant heat shock gene, hsp70, induction via glutamate release with subsequent opening of the NMDA receptor calcium channel. PCP (phencyclidine) and ketamine are noncompetitive blockers of the NMDA calcium channel. They act to prevent significant NMDA receptor excitotoxicity. PCP (20 mg/kg i.p.) and ketamine (60 mg/kg i.p.) both diminished quisqualate and AMPA hsp70 induction in the CA1, CA2, CA3 areas of the hippocampus, in the polymorph area of the dentate gyrus, and in the parietal neocortex. PCP significantly (P < 0.05) diminished kainate hsp70 induction only in the CA1 area and the neocortex. Ketamine failed to reduce kainate hsp70 induction. AMPA receptors appear to result in excitotoxic damage via glutamate release. Glutamate opens NMDA receptor calcium channels which increases intraneuronal calcium levels. Kainate receptors probably mediate excitotoxicity via direct calcium conductance with glutamate release being important in the CA1 area and neocortex.
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PMID:PCP and ketamine inhibit non-NMDA glutamate receptor mediated hsp70 induction. 886 85


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