Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.16.2 (PCP)
 3,761 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A retrospective study of illicit phencyclidine (PCP), which consisted of 94 different cases or 213 individual samples, has shown that one third of both the powder/tablets and green plant material contained the synthetic contaminant 1-piperidinocyclohexanecarbonitrile (PCC). The mole % PCC/PCP ranged from 1 to 68%. The method of analysis was gas chromatography (3% OV-7, 205 degrees C) and in preparation for analysis the sample was dissolved directly in chloroform or extracted from a strongly acidic solution (0.1 N HCl). Using these extraction conditions PCC was found not to undergo measurable decomposition.
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PMID:Contamination of illicit phencyclidine with 1-piperidinocyclohexanecarbonitrile. 744 33

Antiphencyclidine monoclonal antibody binding fragments (anti-PCP Fab) were studied in rats as a possible treatment for phencyclidine (PCP) overdose. Each male Sprague-Dawley rat (n = 4 per group) received an i.v. dose of 1 mg/kg of PCP followed 5 min later (as toxicity maximized) by one of three treatments in a random cross-over design. The treatments were 1 ml of saline, a nonspecific polyclonal human Fab, or a high affinity (Kd = 1.8 nM) anti-PCP monoclonal Fab. The doses of the nonspecific and anti-PCP Fab were 0.3, 1.0 and 3.0 times the mole equivalent (mol-eq) dose of PCP. Changes in locomotor activity and ataxia were the best indicators of PCP-induced behaviors among several time-dependent behavioral changes that were evaluated. PCP administration followed by saline treatment resulted in increases in locomotor activity and ataxia that declined to base line after 35 to 40 min. Anti-PCP Fab at 1.0 and 3.0 times the mol-eq dose of PCP significantly (P < .05) and rapidly reversed PCP-induced behaviors to base-line values. Although the 0.3 mol-eq dose of Fab appeared to slightly decrease the behavioral toxicity, the effects were not statistically different from controls in most cases. No significant effects on PCP-induced behaviors were observed after any dose of the nonspecific Fab. In addition, pharmacological and immunological specificity were tested further by treatment of MK-801 {(+)-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine-}-induced behavioral effects. MK-801 is a PCP-like, noncompetitive N-methyl-D-aspartate receptor antagonist which is structurally unrelated to PCP. The anti-PCP Fab treatment had no effect on MK-801-induced locomotor activity. These data clearly show that anti-PCP Fab is a specific PCP antagonist that can rapidly reverse PCP-induced behavioral toxicity in the rat.
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PMID:Antiphencyclidine monoclonal Fab fragments reverse phencyclidine-induced behavioral effects and ataxia in rats. 876 22

The development of treatment strategies for drug intoxication has been hindered in part by the lack of clinically useful antagonists. Consequently, the major goal of these studies was to determine whether a monoclonal antibody Fab fragment (of IgG) could be used as an effective drug class-selective antagonist and to understand better the dose-response relationships for reversing CNS drug toxicity. Changes in drug-induced locomotor effects in a rat model were used to assess the ability of the antiphencyclidine (anti-PCP) Fab to reverse the behavioral effects of PCP and other potent arylcyclohexylamines. In experiments to determine the pharmacodynamics of Fabinduced antagonism of behavioral effects, the Fab completely reversed all PCP-induced locomotor effects in a Fab dose-dependent manner with a minimal effective dose of 0.18 mole-equivalents of Fab and an ED50 value of about one-third mole-equivalent. The anti-PCP Fab also completely reversed the locomotor effects induced by two other structurally related potent analogs of PCP: 1-[1-(2-thienyl)cyclohexyl]piperidine and N-ethyl-1-phenylcyclohexylamine. In addition, pharmacological and immunological selectivity was further tested by treatment of the behavioral effects induced by the structurally unrelated locomotor stimulant (+)methamphetamine. The antibody did not effectively reverse the effects of methamphetamine-induced locomotor activity. These results indicate that antibody-based medications can be developed to treat toxicity caused by classes of drugs as well as by individual drugs.
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PMID:Pharmacodynamics of a monoclonal antiphencyclidine Fab with broad selectivity for phencyclidine-like drugs. 961 14

Vascular endothelial growth factor (VEGF) is a dimeric protein which induces formation of new blood vessels (angiogenesis) through binding to VEGF-receptor-2 tyrosine kinase (VEGFR2 TK) or KDR (kinase insert domain-containing receptor) on the surface of endothelial cells. Angiogenesis has been shown to be essential for malignancy of tumors; therefore, VEGFR2 TK is a potential therapeutic target for the treatment of cancer. Sequence homology studies indicate that VEGFR2 TK contains three domains: extracellular (ligand-binding domain), transmembrane, and intracellular (catalytic domain). In this work, the catalytic domain of VEGFR2 TK was cloned and expressed in a soluble active form using a baculovirus expression system. In the absence of ligand, the enzyme is shown to catalyze its autophosphorylation in a time-dependent and enzyme-concentration-dependent manner, consistent with a trans mechanism for this reaction. Mass spectrometry analysis revealed incorporation of 5.5 +/- 0.5 mol of phosphate/mole of enzyme (monomer). In addition, the enzyme was shown to catalyze phosphorylation of a synthetic peptide, poly(E4Y). Using poly(E4Y) as substrate, the kinetic constants of both native and phosphorylated enzyme were determined. Enzyme phosphorylation increased catalytic efficiency of the enzyme by at least an order of magnitude. Furthermore, the enzyme was shown to catalyze the reverse reaction using phospho-poly(E4Y) as substrate. Cd2+ was found to be an inhibitor of the enzyme. Kinetic studies revealed that inhibition by Cd2+ was competitive with respect to Mg2+ and noncompetitive with respect to MgATP. These results indicate that Cd2+ competes for a second metal-binding site. Therefore, the reaction catalyzed by this enzyme was treated as a terreactant system. The kinetic mechanism of VEGFR2 TK was elucidated through the use of steady-state kinetic studies. According to these studies, the enzyme binds Mg2+ and MgATP in a random fashion followed by ordered addition of the peptide substrate. The release of product is also ordered, with MgADP being released last. The order of substrate binding was confirmed by using AMP-PCP, a dead-end inhibitor.
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PMID:Characterization and kinetic mechanism of catalytic domain of human vascular endothelial growth factor receptor-2 tyrosine kinase (VEGFR2 TK), a key enzyme in angiogenesis. 984 50

These studies examined the hypothesis that a single large dose of monoclonal anti-phencyclidine (PCP) antibody could provide long-term reductions in brain PCP concentrations despite continuous PCP administration. PCP (18 mg/kg/day, s.c.) was infused to steady-state (24 h) and then a mole-equivalent dose of a short-acting anti-PCP antigen-binding fragment (Fab) or a long-acting anti-PCP IgG was administered i.v. The PCP infusion continued for up to 27 days, even though the binding capacity of the single dose of antibody used should have been saturated within the first day. At selected time points after antibody administration, brain, testis, and serum PCP concentrations were measured. Serum PCP concentrations rapidly increased approximately 100- and 300-fold after Fab or IgG administration, respectively. Based on the antibody-bound PCP concentrations in serum, the functional elimination half-life (t(1/2lambdaZ)) values for PCP-Fab and PCP-IgG complexes were 9.4 h and 15.4 days, respectively. Fab and IgG administration produced a complete removal of PCP from the brain within 15 min. Although brain PCP concentrations were significantly decreased for only 4 h in Fab-treated animals, IgG administration resulted in significant decreases in brain PCP concentrations lasting for at least 27 days. In contrast, testis PCP concentrations were not substantially affected by antibody administration, suggesting that redistribution of PCP from the testis is too slow to benefit from a limited dose of antibody. These results indicate that anti-PCP IgG can preferentially protect the brain for approximately 4 weeks after IgG administration, even when the antibody binding capacity should have been saturated with continuously administered PCP.
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PMID:Anti-phencyclidine monoclonal antibodies provide long-term reductions in brain phencyclidine concentrations during chronic phencyclidine administration in rats. 1068 94

The mechanism of (PCP)Ir-catalyzed transfer-dehydrogenation has been elucidated for the prototypical substrate/acceptor couple, COA/TBE, at 55 degrees C (COA = cyclooctane; TBE = tert-butylethylene). The catalytic cycle may be viewed as the sum of two reactions: (i) hydrogenation of TBE by (PCP)IrH2 and C-H addition of a second mole of TBE to give (PCP)IrH(tert-butylvinyl), and (ii) dehydrogenation of COA by (PCP)IrH(tert-butylvinyl) to give (PCP)IrH2, COE, and TBE. These two stoichiometric reactions have been observed independently and their kinetics determined. The overall catalysis has also been monitored in situ, and (PCP)IrH2 and (PCP)IrH(tert-butylvinyl) have been observed as the resting states; the ratio of these two complexes is found to be proportional to [TBE]2. Based upon the proportionality constant thus obtained and the catalytic rate as a function of [TBE] (which reaches a maximum at ca. 0.3 M), the respective rate constants for the hydrogenation and dehydrogenation segments can be obtained. Good agreement is found between the rates independently obtained from stoichiometric and catalytic runs. Within the overall TBE-hydrogenation reaction, labeling experiments indicate that the rate-determining step is the reductive elimination of TBA (2,2-dimethylbutane) from (PCP)IrH(tert-butylethyl) (which is formed via insertion of TBE into an Ir-H bond of (PCP)IrH2). Based upon considerations of microscopic reversibility, it can be further inferred that the rate-determining step for the alkane dehydrogenations is C-H addition (and not beta-H elimination).
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PMID:Mechanism of alkane transfer-dehydrogenation catalyzed by a pincer-ligated iridium complex. 1282 73

New amine-groups containing tri-block copolymers and micelles that consisting of poly(epsilon-caprolactone)-b-chitooligosaccharide-b-poly(ethylene glycol) (PCL-b-COS-b-PEG, PCP), were synthesized, characterized, and evaluated for delivering doxorubicin (DOX) with or without crosslinked amine groups by genipin. The characteristics of the PCP copolymers of Fourier-transform infrared spectrometry (FT-IR) verify the amine and ester groups of the COS and the PCL of the copolymers, respectively. 1H nuclear magnetic resonance (1H NMR) spectra verify the structures of the PCP copolymers consisting two PCL and PEG polymers reacted onto the COS block. In addition, gel permeation chromatography (GPC) determines the number average molecular weight of the tri-block copolymers (Mn) of approximately 11340 Da/mole. The PCP copolymers can self-assemble to form polymeric micelles at the critical micelle concentration (CMC) of 1.0 microM as determined by the UV-VIS absorption spectra. The mean diameter of the PCP micelles is 90 nm, as determined using a dynamic light-scattering (DLS) analyzer. Moreover, the zeta potentials of PCP micelles change from neutral to cationic state when pH of suspension mediums varied from 7.4 to 3.0. For evaluating delivery characteristics of hydrophobic DOX, it was loaded into PCP micelles with or without crosslinked by genipin. The burst release and release period of DOX for the crosslinked micelles are significantly reduced (P < 0.003, n = 3, for pH = 7.4) and sustained (e.g., 8 days), respectively, than those non-crosslinked ones (e.g., 4 days). In conclusion, new tri-block amine groups containing PCP copolymers are synthesized that can self-assemble as PCP micelles. After post-crosslinked amine groups of DOX loaded the micelles, they can effectively reduce the burst release and sustain the release of DOX at different pH dissolution mediums. Further applications of PCP copolymers and micelles for drug delivery can be explored in future.
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PMID:Characterizing poly(epsilon-caprolactone)-b-chitooligosaccharide-b-poly(ethylene glycol) (PCP) copolymer micelles for doxorubicin (DOX) delivery: effects of crosslinked of amine groups. 1704 97