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)

Phencyclidine (PCP) has been reported to suppress a variety of immune functions in vitro. Because PCP binds with high affinity to both PCP and sigma receptors, the identity of the receptor(s) mediating the immunological effects of PCP is unknown. The aim of the present study was to identify and characterize the sites of PCP action (sigma and/or PCP receptors) in human peripheral blood leukocytes (PBL) using [3H]haloperidol or 1,3 di(2-([5-3H]tolyl)guanidine ([3H]DTG) to specifically label sigma receptors and 3,4-[3H]-(N)-[1-(2-thienyl)-cyclohexyl]-piperidine ([3H]TCP) to specifically label PCP receptors. [3H]Haloperidol binding was saturable and of high affinity with comparable KD values in human PBL (0.44 +/- 0.10 nM) and rat cerebellum (0.51 +/- 0.09 nM). Similarly, [3H]DTG binding was saturable with comparable KD values of 29.5 +/- 3.5 and 26.4 +/- 3.6 nM in rat cerebellum and human PBL, respectively. In contrast, there was a notable absence of [3H]TCP-labeled PCP receptors in human PBL and rat cerebellum. In competition studies, the pharmacologic profile of [3H]haloperidol-labeled sigma receptors in human PBL was virtually identical with that in rat cerebellum (slope, 0.87; correlation coefficient, 0.96); the rank order of potency of competing drugs was haloperidol greater than l-butaclamol = pentazocine greater than d-3-(hydroxyphenyl)-N-(1-propyl)-piperidine greater than DTG = d-butaclamol = d-SKF 10,047 greater than levallorphan greater than or equal to PCP greater than or equal to l-SKF 10,047 greater than TCP greater than MK-801.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Initial identification and characterization of sigma receptors on human peripheral blood leukocytes. 284 60

Transient brain ischemia results in a selective destruction of cell bodies within the hippocampus and cortex. This cellular destruction appears to be mediated through a release of endogenous exictatory amino acids following the ischemic episode, since the neurotoxic effects of ischemia can be attenuated by compounds that have antagonist activity at N-methyl-D-aspartate (NMDA) receptors. In the present study, the protective effects of a novel NMDA receptor antagonist, CGS 19755, were further evaluated by using quantitative autoradiography to characterize adenosine A1, NMDA, PCP, and benzodiazepine receptors in ischemic gerbil brain. Bilateral carotid artery occlusion (20 minutes) resulted in marked decreases (30-60%) in adenosine A1, NMDA, and PCP, but not benzodiazepine, receptors in gerbil forebrain. Postischemic treatment with CGS 19755 was found to completely block the ischemia-induced decreases in brain adenosine and NMDA receptors. [3H]TCP binding in ischemic gerbil brain was also elevated by CGS 19755 treatment; significant differences remained, however, between the CGS 19755-treated and control gerbils. These results indicate that transient brain ischemia produces significant and selective alterations in gerbil forebrain receptor systems. The observed decreases in radioligand binding are probably reflective of an ischemia-induced destruction of forebrain structures. However, there is some evidence that transient ischemia can also cause long-term changes in the affinity of some receptor systems. The postischemic efficacy of CGS 19755 appears to be due to its ability to block the neurotoxic effects of transient ischemia.
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PMID:The novel N-methyl-D-aspartate (NMDA) antagonist CGS 19755 prevents ischemia-induced reductions of adenosine A1, NMDA, and PCP receptors in gerbil brain. 285 Jun 32

The present study provides evidence for the presence of an endogenous ligand for the phencyclidine (PCP) receptor of mammalian brain. Partially purified bovine hippocampal extracts potently and dose dependently inhibit binding to PCP receptors of [3H]N-(1-[2-thienyl]-cyclohexyl)piperidine (TCP), a highly potent and specific ligand of PCP receptors. In addition to demonstrating PCP-like binding properties, the partially purified extract mimics biological actions of PCP upon neurotransmitter release. HPLC fractions active in the [3]TCP binding assay, by contrast to fractions inactive in the binding assay, potently elicited stimulation of spontaneous acetylcholine and dopamine efflux and inhibited NMDA-stimulated release of acetylcholine and dopamine. The transmitter release assay provides validation of a PCP-like physiological activity exerted by bovine hippocampal extracts partially purified by HPLC.
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PMID:An endogenous ligand of the brain sigma/PCP receptor antagonizes NMDA-induced neurotransmitter release. 288 50

Phencyclidine (PCP) is a widely abused drug of the arylcyclohexylamine class which is capable of producing symptoms of acute psychosis in man. PCP interacts with a specific CNS receptor, for which a putative endogenous peptide ligand has been identified. We have investigated whether PCP receptor binding parameters are modulated by activity in central opiate pathways. We have found that chronic administration of both an opiate agonist (etonitazene) and an opiate antagonist (naloxone) are able to decrease the affinity of the PCP receptor for TCP, a thienyl derivative of PCP. Furthermore, naloxone, but not etonitazene, resulted in a significant increase in the Bmax of TCP binding to the PCP receptor. These results suggest that neural activity mediated by CNS opioids systems is capable of affecting the binding parameters of the PCP receptor.
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PMID:Rat brain PCP receptors: alterations in binding parameters following chronic administration of opiate agonists and antagonists. 289 Oct 74

Biochemical and electrophysiological studies have provided evidence that a complex comprising the N-methyl-D-aspartate (NMDA)-type excitatory amino acid (EAA) receptor and the phencyclidine (PCP) recognition site exists in mammalian brain. This complex, which has been compared to that established for the inhibitory amino acid, gamma-aminobutyric acid, and the benzodiazepine anxiolytic, diazepam, is sensitive to the effects of the divalent cation Mg2+, which has suggested the presence of a third, ion channel component. Using a radioreceptor assay for the PCP receptor, L-glutamate (L-Glu) produced a concentration-dependent increase in the binding of [3H]thienyl cyclohexylpiperazine ([3H]TCP) in well washed membranes from rat forebrain. The EAA produced a maximal increase in specific binding of 400%, with an EC50 value of 340 nM. The ability of L-Glu to enhance [3H]TCP binding was 10-fold more potent in the presence of 30 microM Mg2+, which inhibits NMDA-evoked responses in intact tissue preparations and produces a 50% increase in [3H]TCP binding on its own. Analysis of saturation curves indicated that the effect of both L-Glu and Mg2+ could be attributed to an increase in receptor affinity as well as increases in the proportion of a high affinity state of the PCP-binding site. Assessment of the effect of a number of EAAs on basal [3H]TCP binding (well washed membranes in the absence of either L-Glu or Mg2+) showed that the EAA recognition site involved in the effects of L-Glu was the NMDA subtype. Further studies examined a series of compounds thought to interact with either the NMDA or PCP components of the receptor complex under four binding conditions: basal, +Mg2+; +L-Glu; and +Mg2+/L-Glu. These results showed that dissociative anesthetics, such as dexoxadrol and PCP, as well as the novel anticonvulsant MK-801, selectively interact with the high affinity state of the PCP receptor. NMDA antagonists, such as CPP, were also found to inhibit binding to the high affinity state of the PCP receptor, although not as potently as the dissociative anesthetics. Interestingly, the NMDA antagonists did not inhibit any of the binding to the low affinity state of the receptor. The sigma ligands (+/-)-SKF 10,047 and haloperidol recognized two components of [3H]TCP binding only in the presence of L-Glu. The results of the present study are consistent with the finding that agonists of the NMDA receptor induce a high affinity state of the PCP receptor.
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PMID:Interaction of L-glutamate and magnesium with phencyclidine recognition sites in rat brain: evidence for multiple affinity states of the phencyclidine/N-methyl-D-aspartate receptor complex. 289 25

Phencyclidine (PCP) receptors were successfully solubilized from rat forebrain membranes with 1% sodium cholate. Approximately 58% of the initial protein and 20-30% of the high-affinity PCP binding sites were solubilized. The high affinity toward PCP-like drugs, the stereo-selectivity of the sites, and the sensitivity to N-methyl-D-aspartate (NMDA) receptor ligands were preserved. Binding of the potent PCP receptor ligand N-[3H][1-(2-thienyl)cyclohexyl] piperidine ([3H]TCP) to the soluble receptors was saturable (KD = 35 nM), and PCP-like drugs inhibited [3H]TCP binding in a rank order of potency close to that observed for the membrane-bound receptors; the most potent inhibitors were TCP (Ki = 31 nM) and the anticonvulsant MK-801 (Ki = 50 nM). The NMDA receptor antagonist 2-amino-5-phosphonovaleric acid inhibited binding of [3H]TCP to the soluble receptors; glutamate or NMDA diminished this inhibition in a dose-dependent manner. Taken together, the results indicate that the soluble PCP receptor preparation contains the glutamate recognition sites and may represent a single receptor complex for PCP and NMDA, as suggested by electrophysiological data. The successful solubilization of the PCP receptors in an active binding form should now facilitate their purification.
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PMID:Solubilization of rat brain phencyclidine receptors in an active binding form that is sensitive to N-methyl-D-aspartate receptor ligands. 289 2

The anatomical localization of phencyclidine (PCP)/sigma-opiate receptors in rat brain was determined by quantitative light microscopy autoradiography using the new ligand N-(1-[2-thienyl]cyclohexyl) [3H]piperidine ([3H]TCP). TCP is a potent analog of PCP which possesses a higher affinity for PCP/sigma-opiate receptor than does PCP itself. The highest level of [3H]TCP binding was detected in the hippocampus. Intermediate levels were found in frontal cortex, striatum, amygdala and cerebellum. Specific [3H]TCP binding was undetectable in anterior commissure and corpus callosum. The distribution pattern of [3H]TCP binding sites is similar to the pattern obtained with [3H]PCP but more sharply defined. On the basis of its greater potency and specificity, [3H]TCP may prove superior to [3H]PCP as a molecular probe for the study of brain sigma opiate/phencyclidine receptors.
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PMID:Quantitative localization of [3H]TCP binding in rat brain by light microscopy autoradiography. 299 34

The distribution of phencyclidine (PCP) receptors in the rat brain was determined by autoradiography using 1-(1-(2-thienyl)cyclohexyl)piperidine ([3H]TCP). [3H]TCP appeared to bind to PCP receptors as only PCP-like drugs and sigma-opioids inhibited the binding of [3H]TCP. The areas of the rat brain with the highest density of radiolabeled binding sites were the superficial layers of cerebral cortex, hippocampus and dentate gyrus. Moderate densities of binding sites were found in the medial geniculate nuclei, caudate nucleus, nucleus accumbens, interpeduncular nucleus, superior colliculus, periaqueductal gray and cerebellum. Low densities of binding sites were observed in spinal cord, most of the brainstem, the substantia nigra and most of the hypothalamus.
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PMID:Autoradiographic distribution of phencyclidine receptors in the rat brain using [3H]1-(1-(2-thienyl)cyclohexyl)piperidine ([3H]TCP). 301 94

The benzomorphan opioid, SKF 10,047, is the prototypical agonist for the sigma receptor. In this study, pharmacological and autoradiographic analyses reveal that (+)-[3H]SKF 10,047 labels two sites in brain: a high affinity site resembling the sigma receptor and a second site, labeled with lower affinity by (+)-[3H] SKF 10,047, similar to the phencyclidine (PCP) receptor. The drug specificity of the high affinity site for (+)-[3H]SKF 10,047 resembles that of the putative sigma receptor labeled with (+)-[3H]-3-[3-hydroxyphenyl]-N-(1-propyl)piperidine [(+)-[3H]-3-PPP], being potently inhibited by (+)-3-PPP, haloperidol and (+/-)-pentazocine, and demonstrating stereoselectivity for the (+)-isomer of SKF 10,047. In contrast, these drugs are weak in inhibiting binding of (+)-[3H]SKF 10,047 to the low affinity site, whereas PCP analogs, such as 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP) and 1-[1-(m-aminophenyl)cyclohexyl]piperidine (m-NH2-PCP), are potent inhibitors. No stereoselectivity for the isomers of SKF 10,047 is noted at the low affinity binding site. Autoradiographic localizations of high affinity (+)-[3H]SKF 10,047 binding sites closely resemble those of (+)-[3H]-3-PPP labeled sites with high levels of binding in the hippocampal pyramidal cell layer, hypothalamus, pontine and cranial nerve nuclei and cerebellum. By contrast, low affinity (+)-[3H]SKF 10,047 sites are most abundant in nonpyramidal layers of the hippocampus, the cerebral cortex and thalamic nuclei, similar to the distribution of [3H]TCP labeled PCP receptors.
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PMID:Pharmacological and autoradiographic discrimination of sigma and phencyclidine receptor binding sites in brain with (+)-[3H]SKF 10,047, (+)-[3H]-3-[3-hydroxyphenyl]-N-(1-propyl)piperidine and [3H]-1-[1-(2-thienyl)cyclohexyl]piperidine. 301 48

Receptor binding sites for the phencyclidine (PCP) analogue, [3H]TCP, have been localized in the rat and guinea pig central nervous systems by in vitro autoradiography. Quantitation of [3H]TCP binding site densities in rat brain reveals highest levels in the forebrain, in particular the strata oriens and radiatum of the hippocampus, the molecular layer of the dentate gyrus and superficial layers of the cerebral cortex. Moderate levels of binding occur in the amygdala, thalamus, anterior olfactory nucleus, external plexiform layer of the olfactory bulb, olfactory tubercle, geniculate nuclei and deep layers of the cortex. Low levels of binding occur throughout most of the septum, diagonal band, hypothalamus, pons-medulla and cerebellum. Spinal cord grey matter also has low levels of binding. Excitotoxin lesions of the hippocampal formation, which destroy the pyramidal and granule cells, reduce the binding of [3H]TCP to strata radiatum and oriens and the molecular layer of the dentate gyrus by 60% suggesting that [3H]TCP labels intrinsic neurons in these regions. Residual binding is probably on afferent terminals. Ibotenic acid lesions of the caudate-putamen reduce [3H]TCP binding by 70%, indicating that binding sites are localized on intrinsic striatal neurons. 6-Hydroxydopamine lesions do not alter [3H]TCP binding levels in the caudate, suggesting the absence of binding sites on dopaminergic terminals in the caudate.
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PMID:Phencyclidine (PCP) receptors: autoradiographic localization in brain with the selective ligand, [3H]TCP. 302 81


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