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 novel semirigid derivatives (+)-cis-1-[2-phenyl-2-bicyclo[3.1.0]hexyl]piperidine [(+)-8], its enantiomer (-)-8, and (+-)-trans-1-[2-phenyl-2-bicyclo[3.1.0]hexyl]piperidine [(+/-)-9] were synthesized as probes to investigate the mode of interaction of phencyclidine (PCP) with its binding site on the N-methyl-D-aspartate receptor complex. Each target compound was obtained in five steps starting from cyclopent-2-enone. (+)- and (-)-8 were obtained in greater than 98% optical purity through three recrystallizations from ethanol of the (S)-(+)- and (R)-(-)-mandelate salts of intermediate (+-)-cis-2-phenyl-2-bicyclo[3.1.0]hexylamine ([(+/-)-16]. Crystallization of the (R)-(-)-mandelate salt afforded (1R,2R,5S)-(-)-16, whereas the (S)-(+)-mandelate salt afforded (1S,2S,5R)-(+)-16; the absolute configuration was determined by single-crystal X-ray analysis of (-)-16.(R)-(-)-mandelate. Single-crystal X-ray analysis of (+/-)-9-picrate confirmed its trans configuration and provided conformational data. (+)- and (-)-8 and (+/-)-9 were examined for their ability to interact with PCP and sigma binding sites in vitro using [3H]TCP and [3H]pentazocine as radioligands. The binding was compared with that of PCP and contrasted with the rigid symmetrical phencyclidine derivatives cis- and trans-1-[3-phenyl-3-bicyclo[3.1.0]hexyl]piperidines (6 and 7). The results of the study indicated that the conformations of PCP represented by 6-9 are not optimal for potent interaction at either of these sites. Affinities ranged from 582 nM [(+/-)-9] to 29,000 nM [(+)-8] at PCP binding sites and from 1130 nM [(-)-8] to 16,300 nM (7) at sigma sites. In this assay, PCP exhibited affinities of 64.5 nM at PCP and 1090 nM at sigma sites. Qualitative correlation between the sigma and PCP binding data suggests some similarities between these binding sites. An axial phenyl and equatorial piperidine ring with the nitrogen lone pair of electrons antiperiplanar to the phenyl ring has been postulated as the receptor-active conformation of PCP-like ligands at the PCP binding site. Comparison of the binding data of 7-9 with that of the previously described methylcyclohexyl-PCP derivatives allowed its rationalization in terms of this model. It is likely that the lowered affinity in this bicyclo[3.1.0]hexane series is a consequence of nonoptimal geometry (pseudoequatorial phenyl or pseudoboat) for binding as opposed to the presence of steric bulk which proved deleterious in the methylcyclohexyl-PCP derivatives.
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PMID:Synthesis, configuration, and activity of isomeric 2-phenyl-2-(N-piperidinyl)bicyclo[3.1.0]hexanes at phencyclidine and sigma binding sites. 146 99

The synthesis and in vitro sigma receptor activity of the two diastereomers of U50,488 [(+/-)-2], namely, (1R,2S)-(+)- cis-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacet ami de [(+)-1] and (1S,2R)-(-)-cis-3,4-dichloro- N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide [(-)-1], are described. (+)-1 and (-)-1 were synthesized from (+/-)-trans-N-methyl-2-aminocyclohexanol [(+/-)-3]. Pyridinium chlorochromate (PCC) oxidation of the N-t-Boc-protected derivative of (+/-)-3 afforded (+/-)-2-[N- [(tert-butyloxy)carbonyl]-N-methylamino]cyclohexanone [(+/-)-5]. The sequence of enamine formation with pyrrolidine, catalytic reduction, N-deprotection, and optical resolution afforded (1R,2S)-(-)-cis-2-pyrrolidinyl-N-methylcyclohexylamine [(-)-10] and (1S,2R)-(+)-cis-2-pyrrolidinyl-N-methylcyclohexylamine [(+)-10]. The optical purity (greater than 99.5%) of (-)-10 and (+)-10 was determined by HPLC analysis of the diastereomeric ureas formed by reaction with optically pure (R)-alpha-methylbenzyl isocyanate. The absolute configuration of (-)-10 and (+)-10 was determined by single-crystal X-ray diffractometry of the bis-(R)-mandelate salt. Condensation of optically pure (-)-10 and (+)-10 with 3,4-dichlorophenylacetic acid furnished (+)-1 and (-)-1, respectively. Compounds (+)-1, (-)-1, (-)-2, and (+)-2 were compared for their binding affinities at kappa opioid, sigma, D2-dopamine, and phencyclidine (PCP) receptors in competitive binding assays using [3H]bremazocine ([3H]BREM) or [3H]U69,593, [3H]-(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [[3H]-(+)-3-PPP], or [3H]-1,3-di(o-tolyl)guanidine ([3H]DTG), [3H]-(-)-sulpiride [[3H]-(-)SULP], and [3H]-1- [1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP), respectively. In the systems examined, (-)-2 exhibited the highest affinity for kappa receptors, with a Ki of 44 +/- 8 nM. However, (-)-2 also showed moderate affinity for sigma receptors, with a Ki of 594 +/- 3 nM [[3H]-(+)-3-PPP]. The (1R,2R)-(+)-enantiomer, (+)-2, had low affinity for both kappa and sigma receptors, exhibiting Ki values of 1298 +/- 49 nM at kappa ([3H]BREM) and 1270 +/- 168 nM at sigma [[3H]-(+)-3-PPP]. In contrast, the chiral cis compounds (+)-1 and (-)-1 showed high affinity for sigma receptors and negligible affinity for kappa opioid receptors in the [3H]BREM assay. Compound (-)-1 exhibited a Ki of 81 +/- 13 nM at sigma receptors [[3H]-(+)-3-PPP] and 250 +/- 8 nM ([3H]DTG).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Alterations in the stereochemistry of the kappa-selective opioid agonist U50,488 result in high-affinity sigma ligands. 254 74

The cis and trans enantiomers of the 1-(1-methylcyclohexyl)piperidines were prepared from either 3(R)- or 3(S)-methylcyclohexanone through the Bruylents reaction or a modified azide route, respectively. Separation of the intermediate amines 5 and 6 was achieved through chromatography or selective crystallization of a fumarate salt. The cis isomer 2b had about one-third of the affinity of phencyclidine for the PCP receptor. The other isomers were less potent. There was a 40-fold difference between the binding affinity of the cis enantiomers 2a and 2b and a fourfold difference between the affinities of the trans enantiomers 1a and 1b. None of the compounds antagonized the stereotypy induced by phencyclidine in the rotorod assay in mice, after intraperitoneal introduction.
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PMID:Synthesis, pharmacological action, and receptor binding affinity of the enantiomeric 1-(1-phenyl-3-methylcyclohexyl)piperidines. 284 May 2

There are at least four forms of DNA-dependent ATPase in mouse FM3A cells [Tawaragi, Y., Enomoto, T., Watanabe, Y., Hanaoka, F., & Yamada, M. (1984) Biochemistry 23, 529-533]. One of these, ATPase B, has been purified and characterized in detail. During the purification of the enzyme, we encountered the difficulties that the enzyme could not be recovered well from the single-stranded DNA-cellulose column and that the enzyme activity was distributed very broadly. The problems were resolved by the addition of ATP in the elution buffer. The ATPase has a sedimentation coefficient of 5.5 S in both high salt and low salt. The enzyme hydrolyzes rNTPs and dATP, but ATP and dATP are preferred substrates. Adenosine 5'-O-(3-thiotriphosphate) (ATP-gamma-S), 5'-adenylyl methylenediphosphate (AMP-PCP), and 5'-adenylyl imidodiphosphate (AMP-PNP) inhibit the enzyme activity. The enzyme is insensitive to ouabain, oligomycin, novobiocin, and ethidium bromide. A divalent cation (Mg2+ congruent to Mn2+ greater than Ca2+) as well as a nucleic acid cofactor is required for activity. Poly(dT), single-stranded circular DNA, and heat-denatured DNA were very effective. Native DNA was little effective with an efficiency of 29% of that obtained with heat-denatured DNA. In addition, the enzyme showed almost no activity with poly(dA).poly(dT) although it showed very high activity with the noncomplementary combination of poly(dT) and poly(dC), suggesting that ATPase B requires single-stranded DNA for activity. ATP altered the affinity of ATPase B for single-stranded DNA. The interaction of the enzyme with DNA was studied by Sephadex G-200 gel filtration assay.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Purification and characterization of a deoxyribonucleic acid dependent adenosinetriphosphatase from mouse FM3A cells: effects of ribonucleoside triphosphates on the interaction of the enzyme with single-stranded DNA. 301 1

Several pollutants like DDT, atrazine, PCP, and others induce changes of cortisol and glucose levels in serum, variations of the amount of liver glycogen and liver function, and exert changes of the activity of gill ATPase and acetylcholinesterase in brain and serum of carps. There is always a biphasic response, an increase of concentration or enzyme activity for a short time, and a decrease or inhibition of the enzymes after a longer exposure to the pollutants. The time scale, the duration of the period of increase and that of decrease, depends on the concentration and the toxicity of the pollutants. The influence of the pollutants in normal fresh water was compared with the effects occurring in carps acclimated to 1.2% salt water. This condition enables one to show that the carps are more sensitive to the pollutants under this condition. All responses are unspecific. Advice for the use of these tests as criteria for water quality are given.
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PMID:Physiological changes in carps induced by pollution. 622 18

[3H]Ryanodine binding studies of ryanodine receptors in brain membrane preparations typically require the presence of high salt concentrations in assay incubations to yield optimal levels of binding. Here, radioligand binding measurements on rat cerebral cortical tissues were conducted under high (1.0 M KCl) and low (200 mM KCl) salt buffer conditions to determine the effects of ionic strength on receptor binding properties as well as on modulation of ligand binding by Ca2+, Mg2+, beta, gamma-methylene-adenosine 5'-triphosphate (AMP-PCP), and caffeine. In 1.0 M KCl buffer, labeled titration/equilibrium analyses yielded two classes of binding sites with apparent KD (nM) and Bmax (fmol/mg of protein) values of 2.4 and 34, respectively, for the high-affinity site and 19.9 and 157, respectively, for the low-affinity site. Unlabeled titration/equilibrium measurements gave a single high-affinity site with a KD value of 1.9 nM and a Bmax value of 95 fmol/mg of protein. The apparent KD value derived from association and dissociation studies was 20 pM. Equilibrium binding was activated by Ca2+ (KD/Ca2+ = 14 nM), inhibited by Mg2+ (IC50 = 5.0 mM), and unaffected by AMP-PCP or caffeine. In 200 mM KCl buffer conditions, labeled titration analyses gave only a single site with a KD value similar to and a Bmax value 1.8-fold greater than those obtained for the low-affinity site in 1.0 M KCl buffer. In unlabeled titration measurements, the KD value was fivefold lower, whereas the Bmax value was unaffected. The KD value derived from association and dissociation analysis was 2.4-fold greater in 200 mM KCl compared with 1.0 M KCl buffer conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ionic strength dependence of calcium, adenine nucleotide, magnesium, and caffeine actions on ryanodine receptors in rat brain. 818 38

Large amounts of the powerful pesticide sodium pentachlorophenol (Na-PCP) salt have been sprayed over vast areas in central China to control schistosomiasis, a parasitic disease of epidemic proportions. Approximately 6000 tons of Na-PCP are produced in China annually. Dioxins, a class of toxic, persistent compounds, are found as impurities in commercial Na-PCP products. These contaminants are released into the environment and significantly contribute to human exposure to dioxins in China. This study was carried out to determine dioxin levels in environmental and human tissue samples from one schistosomiasis area to evaluate the health risks associated with exposure to Na-PCP. Na-PCP pesticide was applied in 1972, 1973, and again in 1978. A total of approximately 454 tons and 902 tons of 5-ppm Na-PCP in water were sprayed over large land and lake problem schistosomiasis areas, respectively. The groups studied were (1) sprayers or handlers of Na-PCP, (2) persons living in the sprayed areas, and (3) persons living in unsprayed areas 300 km north of the sprayed lake located in a city in the Jiangxi province. Individual whole-blood and breast-milk samples were collected and later pooled for dioxin analysis. Also, a sample of commercial Na-PCP was collected. In addition, sediment samples from the lake where Na-PCP was sprayed were collected from four different sites and one control sample was collected from a non-schistosomiasis area. All of the samples were analyzed by high-resolution gas chromatography/mass spectrometry. A sample of Na-PCP used in schistosomiasis regions was analyzed and levels of 2,3,7,8-substituted dibenzodioxin (PCDD) and dibenzofuran (PCDF) congeners were measured. In addition, the international dioxin toxic equivalent (I-TEQ) value of this sample was calculated. Total I-TEQ of 162 parts per billion (ppb) was found in the Chinese Na-PCP product. A pooled breast-milk sample from mothers, female agricultural workers who were born in the schistosomiasis areas where large amounts of Na-PCP were sprayed, had an I-TEQ of 5,4 parts per trillion (ppt), lipid, which was about double that of mothers from control regions, women born in areas not sprayed with Na-PCP (2.6 ppt, lipid). The dioxin I-TEQ values in human blood ranged from 9.0 (subjects 15 to 19 years of age) to 16.3 ppt, lipid (subjects 35 to 70 years of age) in the whole-blood samples from Na-PCP exposed persons, whereas the general population's whole-blood I-TEQs were 4.8 and 6.4 ppt, lipid, respectively. The PCDD/F congener distribution patterns in four sediment samples from schistosomiasis areas were similar to that of Na-PCP. By comparison of specific "fingerprint" congeners (higher chlorinated dioxins and the closely related dibenzofurans) in Na-PCP, human tissues, and sediment samples, we conclude that the chemical pesticide Na-PCP is a source of environmental and human dioxin exposure in the Chinese schistosomiasis area studied. Although human PCDD/F tissue levels in China are low compared with those in more industrialized countries, the elevated I-TEQ levels in exposed persons are cause for concern.
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PMID:Pesticide application and increased dioxin body burden in male and female agricultural workers in China. 887 40

A rapid method was developed for detecting in soil Desulfitobacterium frappieri strain PCP-1, an anaerobic gram-positive bacterium, isolated from a methanogenic consortium degrading pentachlorophenol. The method involved the establishment of a protocol for extracting total DNA from soil with the least contamination, and the use of the polymerase chain reaction (PCR) to detect strain PCP-1 with primers targeted with PCP-1 16S rRNA. To optimize the DNA extraction conditions, a glass mill homogenizer and a low-salt buffer containing polyvinylpolypyrrolidone were used on a black soil rich in organic matter. Recovered DNA was further purified with phenol/chloroform extractions, ammonium acetate precipitation and a G200 Sephadex gel-filtration column. DNA was extracted from soil supplemented with different concentrations of PCP-1 cells. Detection of PCP-1 was by PCR. The limit of detection was 800 added PCP-1 cells/g dry soil. This level of detection was achieved when the T4 gene-32 protein and 1 microgram soil DNA were added to the PCR mixture followed by a nested PCR. This method is quick, sensitive, and can process several samples at the same time.
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PMID:Rapid method for detecting Desulfitobacterium frappieri strain PCP-1 in soil by the polymerase chain reaction. 923 93

1. The activity of Ca2+ channels is regulated by a number of mechanisms including direct allosteric modulation by intracellular ATP. Since ATP derived from glycolysis is preferentially used for membrane function, we hypothesized that glycolytic ATP also preferentially regulates cardiac L-type Ca2+ channels. 2. To test this hypothesis, peak L-type Ca2+ currents (ICa) were measured in voltage-clamped rabbit cardiomyocytes during glycolytic inhibition (2-deoxyglucose + pyruvate), oxidative inhibition (cyanide + glucose) or both (full metabolic inhibition; FMI). 3. A 10 min period of FMI resulted in a 40.0 % decrease in peak ICa at +10 mV (-5.1 +/- 0.6 versus -3.1 +/- 0.4 pA pF-1; n = 5, P < 0.01). Similar decreases in peak ICa were observed during glycolytic inhibition using 2-deoxyglucose (-6.2 +/- 0.2 versus -3.7 +/- 0.2 pA pF-1; n = 5, P < 0.01) or iodoacetamide (-6.7 +/- 0.3 versus -3.7 +/- 0.2 pA pF-1; n = 7, P < 0.01), but not following oxidative inhibition (-6.2 +/- 0.4 versus -6.4 +/- 0.3 pA pF-1; n = 5, n.s.). The reduction in ICa following glycolytic inhibition was not mediated by phosphate sequestration by 2-deoxyglucose or changes in intracellular pH. 4. Reductions in ICa were still observed when inorganic phosphate and creatine were included in the pipette, confirming a critical role for glycolysis in ICa regulation. 5. With 5 mM MgATP in the pipette during FMI, peak ICa decreased by only 18.4 % (-6.8 +/- 0.6 versus -5.5 +/- 0.3 pA pF-1; n = 4, P < 0.05), while inclusion of 5 mM MgAMP-PCP (beta,gamma-methyleneadenosine 5'-triphosphate, Mg2+ salt) completely prevented the decrease in peak ICa (-6.9 +/- 0.3 versus -6.5 +/- 0.3 pA pF-1; n = 5, n.s.). 6. Together, these results suggest that ICa is regulated by intracellular ATP derived from glycolysis and does not require hydrolysis of ATP. This regulation is expected to be energy conserving during periods of metabolic stress and myocardial ischaemia.
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PMID:Preferential regulation of rabbit cardiac L-type Ca2+ current by glycolytic derived ATP via a direct allosteric pathway. 967 64

Glutapyrone, a disodium salt of 2-(2,6-dimethyl-3,5-diethoxycarbonyl-1,4-dihydropyridine-4-carboxamido)- glutaric acid, is a representative of a novel 'class' of amino acid-containing 1,4-dihydropyridine (DHP) compounds developed at the Latvian Institute of Organic Synthesis, Riga, Latvia. Conceptually, the glutapyrone molecule can be regarded as a dipeptide-mimicking structure formed by the "free" amino acid (glutamate) moiety and "crypto" (built into the DHP cycle) amino acid ("GABA") elements. Both of these amino acids are joined by the peptide bond. This compound unlike classical DHPs lacks calcium antagonistic or agonistic properties. Our previous studies revealed a profound and long-term anticonvulsant, stress-protective and neurodeficit-preventive activities of glutapyrone. In view of structural properties the role of glutamatergic mechanisms in the mediation of central effects of glutapyrone was considered. In the present study glutapyrone at the concentration range of 1 microM(-1) mM failed to effect both NMDA ([3H]TCP) and non-NMDA ([3H]KA and [3H]AMPA) receptor ligand binding in the rat cortical membranes in vitro. The compound markedly enhanced motor hyperactivity induced by the NMDA antagonist PCP and the dopamine releasing compound D-amphetamine in the rats. Glutapyrone displayed activity in a variety of animal models relevant for affective/depressive disorders in humans i.e. reserpine-induced ptosis and hypothermia, forced swimming test and open field test. These data indicate that the unusually "broad" pharmacological spectrum of glutapyrone might involve concomitant actions on multiple neurotransmitter systems, particularly, GABA-ergic and the catecholamines. It is discussed whether these functional properties are secondary to action on intracellular events, predominantly, G protein-related since glutapyrone appears to lack direct interactions with a number of receptors including ionotropic glutamate and GABA(A)/Bzd receptors.
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PMID:"Atypical" neuromodulatory profile of glutapyrone, a representative of a novel 'class' of amino acid-containing dipeptide-mimicking 1,4-dihydropyridine (DHP) compounds: in vitro and in vivo studies. 992 26


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