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 synthesis and chemical resolution of cis- and trans-fused 8a-phenyldecahydroquinolines 3 and 4 are described together with the affinity of the four optically pure compounds for the PCP recognition site of the NMDA receptor complex. These compounds were also evaluated for their antagonistic effects on cGMP levels in male Swiss Webster mice, and (-)-4 was found to exhibit in vivo potency comparable to that of MK-801. The results of the binding studies are interpreted in terms of a preferred orientation of PCP's N-H bond in binding to its NMDA receptor-associated recognition site.
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PMID:Synthesis and biological activity of 8a-phenyldecahydroquinolines as probes of PCP's binding conformation. A new PCP-like compound with increased in vivo potency. 131 71

(+/-)-3-Carboxy-5-phosphono-1,2,3,4-tetrahydroisoquinoline (SC-48981), a conformationally restricted analog of the potent competitive N-methyl-D-aspartate (NMDA) antagonist, 2-amino-5-phosphonopentanoate (AP-5), potently inhibited the binding of [3H]glutamate to the N-methyl-D-aspartate (NMDA) receptors with a Ki of 1.6 mcM, but with minimal affinity for kaininate and quisqualate receptors (Ki greater than 50 mcM), in vitro. Consistent with its ability to antagonize the NMDA receptor, SC-48981 decreased the binding of [3H]glycine and [3H]TCP [1-(2-thienyl)cyclohexylpiperidine] to the NMDA-associated glycine and phencyclidine (PCP) recognition sites, in vitro. SC-48981 attenuated levels of basal cGMP and harmaline-induced increases in levels of cGMP in the mouse cerebellum, in vivo, in a competitive manner, with ED50 values of 5.5 and 8.7 mg/kg, i.p. Direct intracerebellar injection of SC-48981 (0.5 microgram) attenuated increases in levels of cGMP induced by central injection of the NMDA-associated glycine receptor agonist, D-serine and by NMDA itself. Parenteral administration of SC-48981 (25 mg/kg, s.c.) decreased basal levels of cGMP for up to 3 h. These results indicate that SC-48981 represents a novel bioavailable competitive NMDA antagonist with a long duration of action.
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PMID:Characterization of 3-carboxy-5-phosphono-1,2,3,4-tetrahydroisoquinoline (SC-48981), a potent competitive N-methy-D-aspartate (NMDA) receptor antagonist, in vitro and in vivo. 135 28

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

Nerve growth factor (NGF) rapidly increases the cyclic GMP (cGMP) level about 2-3-fold and enhances the cGMP phosphodiesterase (PDE) activity about 2-fold in rat pheochromocytoma PC12 cells. No changes in the level of cyclic AMP (cAMP) and in the activity of cAMP PDE were found. GTP and a nonhydrolysable analog of GTP, GMP-PCP, at 100 microM, were able to mimic the effect of NGF on the cGMP PDE activity. These results suggest that the cGMP system may be one of the second messengers of NGF action in PC12 cells.
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PMID:Nerve growth factor increases the cyclic GMP level and activates the cyclic GMP phosphodiesterase in PC12 cells. 246 Mar 74

Using a 'patch-clamp' method in the 'inside-out' configuration, ATP, ADP, AMP-PCP and AMP-PNP have been shown to increase the cGMP-dependent component of the rod plasma membrane conductance 2-4-fold and GTP, GDP but not GMP or nonhydrolyzable GTP analogs GMP-PNP and GTP-gamma-S to abolish the ATP action. The ATP and GTP effects were observed at [EDTA] = 1 mM when magnesium and calcium ions were absent. In about half of the experiments the cGMP-dependent conductance was shown to be increased by cAMP in the micromolar concentration range by 10-50%, the cAMP action did not depend on the presence of nucleoside triphosphates. In vivo ATP, GTP and cAMP are assumed to modulate the sensitivity of the photoreceptor plasma membrane to cGMP.
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PMID:The effect of ATP, GTP and cAMP on the cGMP-dependent conductance of the fragments from frog rod plasma membrane. 253 57

Measurements of calcium uptake and cyclic GMP production by cerebellar granule cells grown in primary culture demonstrated that ethanol preferentially inhibited N-methyl-D-aspartate (NMDA) receptor-gated cation channel function. Concentrations of ethanol as low as 10 mM inhibited NMDA-stimulated Ca2+ uptake by greater than 30%, and ethanol also inhibited NMDA-stimulated (Ca2+-dependent) cyclic GMP accumulation in a similar, dose-dependent manner. Responses to kainate were significantly less sensitive to ethanol. Studies using various concentrations of NMDA, as well as phencyclidine (PCP) and glycine, suggested that ethanol affected the "coagonist" binding site of the NMDA receptor-channel complex, rather than the PCP recognition site.
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PMID:N-methyl-D-aspartate receptors and ethanol: inhibition of calcium flux and cyclic GMP production. 254 53

1. As reported for many other PCP receptor actions, the pharmacological profile of PCP receptor agonists and NMDA receptor antagonists were similar with regard to their effects on cerebellar cGMP levels in vivo. 2. PCP receptor agonists act to increase mesocortical dopamine (DA) metabolism and release. 3. This receptor action is stereospecific and is both dose- and time-dependent. 4. The actions of PCP on DA metabolism appear to involve PCP receptors both in the ventral tegmental area (VTA) and the cortical nerve terminal regions. 5. In contrast to many other systems which have been studied, competitive NMDA antagonists do not act in a manner similar to PCP agonists, with regard to mesocortical DA metabolism. 6. Sigma receptor ligands and NMDA agonists also do not alter mesocortical DA metabolism. 7. These data suggest that the PCP receptor population which modulates mesocortical dopaminergic neurons is not coupled to NMDA receptors.
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PMID:NMDA-coupled and uncoupled forms of the PCP receptor: preliminary in vivo evidence for PCP receptor subtypes. 254 81

In primary cultures of cerebellar granule cells excitatory amino acid recognition sites are coupled with the stimulation of inositol phospholipid (PI) hydrolysis, cGMP formation and 45Ca2+ uptake. Mg2+, 2-amino-5-phosphonovalerate (APV) and phencyclidine (PCP) potently inhibit signal transduction in response to N-methyl-D-aspartate (NMDA), glutamate (GLU) and aspartate (ASP). Activation by quisqualate (QUIS) is transduced selectively into stimulation of PI hydrolysis and this response is not sensitive to inhibition by Mg2+, APV and PCP. Activation by kainate (KA) is transduced into potent stimulation of cGMP formation and 45Ca2+ uptake. Transduction of KA signal is not affected by Mg2+ and is relatively insensitive to PCP and APV.
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PMID:Excitatory amino acid signal transduction in cerebellar cell cultures. 288 6

Phencyclidine (PCP) and some of its pharmacological congeners inhibit the signal transduction at specific excitatory amino acid receptors of cerebellar granule cells in primary cultures. These drugs do not bind to the transmitter recognition sites, and affinity of this specific binding site is increased by the presence of the transmitter bound to its recognition sites. PCP inhibits phosphatidylinositol phosphate hydrolysis mediated by Mg2+-sensitive glutamate receptors (GP1) but not that mediated by Mg2+-insensitive glutamate receptors (GP2). In addition, PCP inhibits Ca2+ influx and cGMP formation mediated by the activation of Mg2+-sensitive glutamate receptors (GC1) but not that mediated by Mg2+-insensitive glutamate receptors (GC2). In this cell culture the activation of phosphatidylinositol phosphate hydrolysis by muscarinic receptor agonists is not affected by PCP. Since PCP inhibits noncompetitively GP1 and GC1 signal transduction it may act as a negative allosteric modulator of signal transduction at both receptors. The pharmacological profile of PCP and its congeners delimits a class of drugs modulating allosterically the action of the primary transmitter at GP1 and GC1 receptors. These drugs need the presence of the transmitter to act and they cannot be termed inverse agonists because they are devoid of activity in the absence of the transmitter; moreover, they do not bind to the transmitter recognition site nor do they prevent the transmitter binding to its recognition sites.
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PMID:Phencyclidine is a negative allosteric modulator of signal transduction at two subclasses of excitatory amino acid receptors. 303 32

Intracellular ATP-dependent Ca2+-sequestration mechanisms were studied in isolated dispersed rat pancreatic acini following treatment with saponin or digitonin to disrupt their plasma membranes. In the presence of 45Ca2+ concentrations less than 10(-6) mol/liter, addition of 5 mmol/liter ATP caused a rapid increase in 45Ca2+ uptake exceeding the control by fivefold. ADP mimicked the ATP effect by 50 to 60%, whereas other nucleotides such as AMP-PNP, AMP-PCP, CTP, UTP, ITP, GTP, cAMP and cGMP did not. Maximal ATP-promoted Ca2+ uptake was obtained at 10(-5) mol/liter Ca2+. Inhibition of Ca2+ uptake by mitochondrial inhibitors was dependent on the Ca2+ concentration, indicating the presence of different Ca2+ storage systems. Whereas the apparent half-saturation constant found for mitochondrial Ca2+ uptake was approximately 4.5 X 10(-7) mol/liter, in the presence of antimycin and oligomycin (nonmitochondrial uptake) it was approximately 1.4 X 10(-8) mol/liter. In the absence of Mg2+ both ATP- and ADP-promoted Ca2+ uptake was nearly abolished. The Ca2+ ionophore and mersalyl blocked Ca2+ uptake, Electron microscopy showed electron-dense precipitates in the rough endoplasmic reticulum of saponin-treated cells in the presence of Ca2+, oxalate and ATP, which were absent in intact cells and in saponin-cells without ATP or pretreated with A23187. The data suggest the presence of mitochondrial and nonmitochondrial ATP-dependent C2+ storage systems in pancreatic acini. The latter is likely to be located in the rough endoplasmic reticulum.
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PMID:Calcium uptake into acini from rat pancreas: evidence for intracellular ATP-dependent calcium sequestration. 680 Dec 63


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