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 N-methyl-D-aspartate receptor blockade on two major variants of rabbit eyeblink conditioning were evaluated using a selective noncompetitive antagonist, [5R, 10S]-[+]-5-methyl-10, 11-dihydro-5H-dibenzo[a, d] cyclo-hepten-5,10-imine hydrogen maleate; dizocilpine (MK-801) or phencyclidine (PCP), a drug of abuse. Either MK-801 or PCP (given daily) impaired rabbits' ability to associate tone conditioned stimuli with airpuff unconditioned stimuli, with the severity of impairment exhibiting clear dose and task dependencies. Trace-conditioned rabbits given > or = 80 micrograms/kg of MK-801 or > or = 1.0 mg/kg of PCP failed to reach a criterion of 80% conditioned responses during training, with significant impairments seen at intermediate doses. Delay-conditioned rabbits, although dose-dependently slowed, successfully acquired the task, even when given doses of MK-801 or PCP that completely blocked acquisition in trace conditioning. Additionally, even low doses of MK-801 (10 micrograms/kg) or of PCP (0.1 mg/kg) severely altered conditioned response timing in trace but not in delay conditioning, resembling effects observed after hippocampal lesions. Doses of MK-801 or PCP that impaired acquisition also severely impaired extinction of both trace- and delay-conditioned eyeblink responses. However, neither MK-801 nor PCP altered retention or timing of previously learned responses. Higher doses of MK-801 (> or = 200 micrograms/kg) or of PCP (> or = 2.0 mg/kg) dose-dependently impaired unconditioned response performance, although lower doses of MK-801 (< or = 160 micrograms/kg) or of PCP (< or = 1.0 mg/kg) had no effects on unconditioned responses or on non-associative pseudoconditioned responses. The deficits observed indicate that although not necessary for retention, N-methyl-D-aspartate receptor activation may facilitate acquisition of delay-conditioning. N-methyl-D-aspartate receptor activation appears to be necessary for acquisition of trace conditioning, and for extinction in either paradigm.
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PMID:N-methyl-D-aspartate receptors in associative eyeblink conditioning: both MK-801 and phencyclidine produce task- and dose-dependent impairments. 915 3

We investigated the effects of a schizophrenomimetic drug, phencyclidine (PCP), on substance P (SP) contents in the discrete rat brain areas using an enzyme-immunoassay for SP. The acute intraperitoneal (i.p.) administration of PCP (10 mg/kg), which is a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) type glutamate receptor and a dopamine uptake inhibitor, reduced the concentration of the peptide in the prefrontal cortex, limbic forebrain, striatum, and substantia nigra, but not in the ventral tegmental area, at 60 or 120 min postinjection. A selective noncompetitive NMDA antagonist, dizocilpine hydrogen maleate ((+)-MK-801) (1 mg/kg, i.p.), also caused a decrease in the SP content in the prefrontal cortex and limbic forebrain but failed to alter the content in the other areas studied 30 min thereafter. Dopamine agonists, methamphetamine (4.8 mg/kg, i.p.) and apomorphine (4.4 mg/kg, i.p.), diminished the SP contents in the striatum and substantia nigra 60 min after their injection without effects in the prefrontal cortex, limbic forebrain, and ventral tegmental area. Furthermore, pretreatment with haloperidol (1 mg/kg, i.p.), a D2 preferable dopamine receptor antagonist and a typical antipsychotic, blocked the ability of PCP to decrease the SP concentrations in the substantia nigra but not in the prefrontal cortex. PCP, therefore, might diminish the SP levels by NMDA receptor-mediated and dopamine-independent mechanisms in the prefrontal cortex and limbic forebrain, but by NMDA receptor-independent and dopamine-dependent mechanisms in the striatum and substantia nigra. The haloperidol-insensitive reduction of the frontal SP could be involved in certain neuroleptic-resistant symptoms of PCP-treated animals, PCP psychosis, or schizophrenia.
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PMID:Differential effects of haloperidol on phencyclidine-induced reduction in substance P contents in rat brain regions. 1065 39

Molecular mechanics calculations using MM3-92 and ab initio quantum mechanical calculations using SPARTAN 5.0 were performed on the structurally similar PCP and BTCP, in which only the latter has a cocaine-like pharmacological profile as a dopamine reuptake blocker. Calculations were also performed on BTCP analogs with a methyl group in various positions of the cyclohexane ring. The results for the cis-2-methyl compound, which retains good pharmacological activity, allowed us to determine that an aryl-axial conformer is the biologically active form for at least some of the compounds in this series. However, an aryl-equatorial conformer presents the identical pharmacophore, as shown by superposition of the two conformers. X-ray crystallographic structures were also obtained for BTCP and related compounds with a 2-methyl group on the cyclohexane ring, with reasonable agreement between the computational and experimental results. Superposition studies were performed with two rigid analogs of cocaine which illustrate the optimal orientations of the ammonium hydrogen for monoamine transporters. There is excellent agreement between a 'back-bridged' cocaine analog that is optimal as a dopamine reuptake blocker and the previously proposed biologically active conformer of methylphenidate. However, BTCP is found to be a better fit to the 'front-bridged' cocaine analog that is optimal for a serotonin reuptake blocker.
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PMID:Conformational preferences of the potent dopamine reuptake blocker BTCP and its analogs and their incorporation into a pharmacophore model. 1072 2

(+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (4, LY354740), a highly selective and orally active group II metabotropic glutamate receptor (mGluR) agonist, has increased interest in the study of group II mGluRs. Our interest focused on a conformationally constrained form of compound 4, because it appeared that the rigid form resulted in not only selectivity for group II mGluR but was orally active. Therefore, we introduced a fluorine atom to compound 4, based on the molecular size (close resemblance to hydrogen atom) and electronegativity (effects on the electron distribution in the molecule) of this atom and carbon-fluorine bond energy. Compound (+)-7 (MGS0008), the best compound among 3-fluoro derivatives 7-10, retained the agonist activity of compound 4 for mGluR2 and mGluR3 ((+)-7: EC(50) = 29.4 +/- 3.3 nM and 45.4 +/- 8.4 nM for mGluR2 and mGluR3, respectively; 4: EC(50) = 18.3 +/- 1.6 nM and 62.8 +/- 12 nM for mGluR2 and mGluR3, respectively) and increased the oral activity of compound 4 ((+)-7: ED(50) = 5.1 mg/kg and 0.26 mg/kg for phencyclidine (PCP)-induced hyperactivity and PCP-induced head-weaving behavior, respectively; 4: ED(50) = >100 mg/kg and 3.0 mg/kg for PCP-induced hyperactivity and PCP-induced head-weaving behavior, respectively). In addition, a compound [(3)H]-(+)-7 binding study using mGluR2 or 3 expressed in CHO cells was successful ((+)-7: K(i) = 47.7 +/- 17 nM and 65.9 +/- 7.1 nM for mGluR2 and mGluR3, respectively; 4: K(i) = 23.4 +/- 7.1 nM and 53.5 +/- 13 nM for mGluR2 and mGluR3, respectively). On the basis of a successful result of compound 7, we focused on the introduction of a fluorine atom on the C6 position of compound 4. (1R,2S,5R, 6R)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid ((-)-11) exhibited a high degree of agonist activity for group II mGluRs equal to that of compound 4 or 7 ((-)-11: K(i) = 16.6 +/- 5.6 and 80.9 +/- 31 nM for mGluR2 and mGluR3, respectively). Our interest shifted to modification on CH(2) at C4 position of compound 11, since replacement of the CH(2) group with either an oxygen atom or sulfur atom yielded compound 5 or 6, resulting in increased agonist activity. We selected a carbonyl group instead of CH(2) at the C4 position of compound 11. The carbonyl group might slightly change the relative conformation of three functional groups, the amino group and two carboxylic acids, which have important roles in mediating the interaction between group II mGluRs and their ligand, compared with the CH(2) group of 4, oxygen atom of 5, and sulfur atom of 6. (1R,2S,5S,6S)-2-Amino-6-fluoro-4-oxobicyclo[3.1. 0]hexane-2,6-dicarboxylic acid monohydrate ((+)-14, MGS0028) exhibited a remarkably high degree of agonist activity for mGluR2 (K(i) = 0.570 +/- 0.10 nM) and mGluR3 (K(i) = 2.07 +/- 0.40 nM) expressed in CHO cells but not mGluR4, 6, 7, 1a, or 5 expressed in CHO cells (K(i) = >100 000 nM). Furthermore, compound (+)-14 strongly inhibited phencyclidine (PCP)-induced head-weaving behavior (ED(50) = 0.090 microg/kg) and hyperactivity (ED(50) = 0.30 mg/kg) in rats. Thus, (+)-7 and (+)-14 are potent, selective, and orally active group II mGluR agonists and might be useful not only for exploring the functions of mGluRs but in the treatment of schizophrenia.
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PMID:Synthesis, SARs, and pharmacological characterization of 2-amino-3 or 6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent, selective, and orally active group II metabotropic glutamate receptor agonists. 1112 99

(PCP)Ir(H)2 (PCP = eta3-1,3-C6H3(CH2PR2)2) complexes are highly effective catalysts for the dehydrogenation of alkanes; in particular, they are the first efficient molecular catalysts for alkane dehydrogenation that do not require a sacrificial hydrogen acceptor. Using density functional theory/effective core potential methods, we have examined C-H bond cleavage in alkanes and arenes by both (PCP)Ir and (PCP)Ir(H)2. C-H addition to the dihydride is accompanied by loss of H2; both associative and dissociative pathways for this exchange reaction have been examined. The energetic barrier (deltaE(is not equal)) for associative displacement of H2 by benzene is much lower than the barrier for a dissociative pathway involving initial loss of H2; however, the pathways have very comparable free energy barriers (deltaG(is not equal)). Extrapolation to the higher temperatures, bulkier phosphine ligands, and the alkane substrates used experimentally leads to the conclusion that the pathway for the "acceptorless" dehydrogenation of alkanes is dissociative. For hydrocarbon/hydrocarbon exchanges, which are required for transfer-dehydrogenation, dissociative pathways are calculated to be much more favorable than associative pathways. We emphasize that it is the free energy, not just the internal energy or enthalpy, that must be considered for elementary steps that show changes in molecularity.
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PMID:DFT/ECP study of C-H activation by (PCP)Ir and (PCP)Ir(H)2(PCP=eta3-1,3-C6H3(CH2PR2)2). Enthalpies and free energies of associative and dissociative pathways. 1120 83

Neuroprotective and biobehavioral properties of a series of novel open chain MK-801 analogs, as well as their structure-activity relationships have been investigated. Three groups of compounds were synthesized: monobenzylamino, benzhydrylamino, and dibenzylamino (DBA) analogs of MK-801. It was revealed that DBA analogs exhibit pronounced glutamate-induced calcium uptake blocking properties and anti-NMDA activity. The hit compound of DBA series, NT-1505, was investigated for its ability to improve cognition functions in animal model of Alzheimer's disease type dementia, simulated by treating animals with cholinotoxin AF64A. The results from an active avoidance test and a Morris water maze test showed that experimental animals, treated additionally with NT-1505, exhibited much better learning ability and memory than the control group (AF64A treated) and close to that of the vehicle group of animals (treated with physiological solution). Study of NT-1505 influence on locomotor activity revealed that it is characterized by a spectrum of behavioral activity radically different from that of MK-801, and in contrast to the latter one does not produce any psychotomimetic side effects in the therapeutically significant dose interval. The computed docking of MK-801 and its flexible analogs on the NMDA receptor elucidated the crucial role of the hydrogen bond formed between these compounds and the asparagine residue for magnesium binding in the NMDA receptor. It was suggested that strong hydrophobic interaction between MK-801 and the hydrophobic pocket in the NMDA receptor-channel complex determines much higher irreversibility of this adduct compared to the intermediates formed between this site and Mg ions or flexible DBA derivatives, which might explain the absence of PCP-like side effects of the latter compounds.
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PMID:Neuroprotective and cognition-enhancing properties of MK-801 flexible analogs. Structure-activity relationships. 1146 74

Competition for molecular hydrogen exists among hydrogen-utilizing microorganisms in anoxic environments, and evidence suggests that lower hydrogen concentrations are observed with more energetically favorable electron-accepting processes. The transfer of electrons to organochlorines via reductive dehalogenation reactions plays an important role in hydrogen dynamics in impacted systems. We studied the flux of aqueous hydrogen concentrations in methanogenic sediment microcosms prior to and during reductive dehalogenation of a variety of substituted chlorophenols (CP) and tetrachloroethene (perchloroethylene, PCE). Mean hydrogen concentrations during reductive dehalogenation of 2,4-CP, 2,3,4-CP, and PCP were 3.6 nM, 4.1 nM, and 0.34 nM, respectively. Sediment microcosms that were not dosed with chlorophenols yet were actively methanogenic maintained a significantly higher mean hydrogen concentration of 9.8 nM. During active PCE dehalogenation, sediment microcosms maintained a mean hydrogen concentration of 0.82 nM. These data indicate that during limiting hydrogen production, the threshold ecosystem hydrogen concentration is controlled by microbial populations that couple hydrogen oxidation to thermodynamically favorable electron accepting reactions, including reductive dehalogenation of chloroaromatic and chloroaliphatic compounds. We also present revised estimates for the Gibbs free energy available from the reductive dehalogenation of a variety of substituted chlorophenols based on recently published values of vapor pressure, solubility, and pKa for these compounds.
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PMID:H2 consumption during the microbial reductive dehalogenation of chlorinated phenols and tetrachloroethene. 1294 58

Reductive dechlorination of chlorophenols (Pentachlorophenol, three tetrachlorophenols (TeCPs), six trichlorophenols (TCPs)) with zero valent zinc was examined through batch experiments. Zinc showed much higher reactivity towards PCP than iron and amended iron indicating that zero valent zinc can be a good candidate for reductive dechlorination of chlorinated phenols. Chlorophenols were sequentially dechlorinated and less chlorinated phenols were identified as reduction products. The mass balance was not complete, indicating that by-products are important and/or that products being measured were lost by unknown pathways. The dechlorination rate of the chlorinated phenols usually followed the order: PCP > TeCPs > TCPs. Among the TeCP and TCP isomers, the reactivity was in the order of 2,3,4,5-TeCP > 2,3,4,6-TeCP > 2,3,5,6-TeCP and 2,3,4-TCP > 2,3,6-TCP > 2,3,5-TCP > 2,4,6-TCP > 2,4,5-TCP > 3,4,5-TCP. The first order reaction rates varied by one order of magnitude or more, depending on the chlorines positions on a phenol ring. A regioselectivity was observed and daughter compound distributions could be rationalized by a mechanism in which radical intermediates were more stabilized by chlorine and hydroxyl groups than by hydrogen; positions alpha to the radical were found to be the most important in stabilization, followed by beta-positions.
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PMID:Dechlorination of chlorinated phenols by zero valent zinc. 1497 41

Reaction of bis(phosphinite) PCP iridium pincer complexes (p-XPCP)IrHCl (5a-f) [X = MeO (5a), Me (5b), H (5c), F (5d), C(6)F(5) (5e), Ar(F)(= 3,5-bis(trifluoromethyl)phenyl) (5f)] with NaOtBu in neat cyclooctane (COA) generates 1:1 mixtures of the respective (p-XPCP)IrH(2) complexes 4a-f and the cyclooctene (COE) olefin complexes (p-XPCP)Ir(COE) (6a-f) at 23 degrees C. At higher temperatures, complexes 4 and 6 are equilibrated because of the degenerate transfer dehydrogenation of COA with free COE (6 + COA right harpoon over left harpoon 4 + 2COE), as was shown by temperature-dependent equilibrium constants and spin saturation transfer experiments at 80 degrees C. At this temperature, the COE complexes 6 exchange with free COE on the NMR time scale with the more electron-deficient complexes 6 exchanging COE faster. The exchange is dissociative and zero order in [COE]. Further analysis reveals that the stoichiometric hydrogenation of COE by complex 4f, and thus the separated back reaction 4f + 2COE --> 6f + COA proceeds at temperatures as low as -100 degrees C with the intermediacy of two isomeric complexes (p-Ar(F)PCP)Ir(H)(2)(COE) (8f, 8f'). COE deuteration with the perdeuterated complex 4f-d(38) at -100 degrees C results in hydrogen incorporation into the hydridic sites of complexes 8f,8f'-d(38) but not in the hydridic sites of complex 4f-d(38), thus rendering COE migratory insertion in complexes 8f,8f' reversible and COE coordination by complex 4f rate-determining for the overall COE deuteration.
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PMID:Mechanistic studies of the transfer dehydrogenation of cyclooctane catalyzed by iridium bis(phosphinite) p-XPCP pincer complexes. 1528 24

The p-methoxy-substituted pincer-ligated iridium complexes, (MeO-(tBu)PCP)IrH(4) ((R)PCP = kappa(3)-C(6)H(3)-2,6-(CH(2)PR(2))(2)) and (MeO-(iPr)PCP)IrH(4), are found to be highly effective catalysts for the dehydrogenation of alkanes (both with and without the use of sacrificial hydrogen acceptors). These complexes offer an interesting comparison with the recently reported bis-phosphinite "POCOP" ((R)POCOP = kappa(3)-C(6)H(3)-2,6-(OPR(2))(2)) pincer-ligated catalysts, which also show catalytic activity higher than unsubstituted PCP analogues (Gottker-Schnetmann, I.; White, P.; Brookhart, M. J. Am. Chem. Soc. 2004, 126, 1804). On the basis of nu(CO) values of the respective CO adducts, the MeO-PCP complexes appear to be more electron-rich than the parent PCP complexes, whereas the POCOP complexes appear to be more electron-poor. However, the MeO-PCP and POCOP ligands are calculated (DFT) to show effects in the same directions, relative to the parent PCP ligand, for the kinetics and thermodynamics of a broad range of reactions including the addition of C-H and H-H bonds and CO. In general, both ligands favor (relative to unsubstituted PCP) addition to the 14e (pincer)Ir fragments but disfavor addition to the 16e complexes (pincer)IrH(2) or (pincer)Ir(CO). These kinetic and thermodynamic effects are all largely attributable to the same electronic feature: O --> C(aryl) pi-donation, from the methoxy or phosphinito groups of the respective ligands. DFT calculations also indicate that the kinetics (but not the thermodynamics) of C-H addition to (pincer)Ir are favored by sigma-withdrawal from the phosphorus atoms. The high nu(CO) value of (POCOP)Ir(CO) is attributable to electrostatic effects, rather than decreased Ir-CO pi-donation or increased OC-Ir sigma-donation.
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PMID:Highly effective pincer-ligated iridium catalysts for alkane dehydrogenation. DFT calculations of relevant thermodynamic, kinetic, and spectroscopic properties. 1546 3


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