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)

To compare the actions of prototypic drugs which are selective for phencyclidine and sigma receptors, the electrophysiological effects of phencyclidine (PCP),3-[3-hydroxyphenyl]-N-(1-propyl)piperidine [+)3-PPP), and 1,3-di(2-tolyl)guanidine (DTG) on CA1 hippocampal pyramidal neurons were examined. A wide range of concentrations of drug was tested to differentiate specific, receptor-mediated effects from nonselective, anesthetic-like actions. At relatively large concentrations (0.1-1 mM), each compound reversibly increased the threshold of action potentials driven by Schaffer collaterals, the duration of action potentials and membrane resistance. The low potencies and rank order of potency suggested that phencyclidine, (+)3-PPP, and DTG were not acting through either high affinity sigma or phencyclidine receptors. These compounds did have receptor-mediated effects at smaller concentrations. Since none of the compounds affected evoked excitatory or inhibitory postsynaptic potentials (EPSP or IPSP) or driven action potentials at subanesthetic concentrations (less than 100 microM), no evidence was found to support the hypothesis that the actions of phencyclidine result from enhanced release of transmitter, caused by the inhibition of a presynaptic potassium conductance. As observed in other neurons, phencyclidine blocked excitations in CA1 pyramidal cells mediated by N-methyl-D-aspartic acid (NMDA) at behaviorally relevant concentrations (1-10 microM). However, (+)3-PPP (1 microM-1 mM) enhanced the pyramidal cell response to NMDA. Alone, DTG did not effect the NMDA-induced response but did inhibit the enhancement induced by (+)3-PPP. The agonist and antagonist actions of the sigma-selective ligands, (+)3-PPP and DTG, suggests that they modify NMDA-induced responses by acting at the sigma receptor.
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PMID:Comparison of the actions of phencyclidine and sigma ligands on CA1 hippocampal pyramidal neurons in the rat. 284 30

Beef heart mitochondrial ATPase (F1) catalyzes the hydrolysis of the ATP analog adenyl-5-yl imidodiphosphate (AMP-PNP). The reaction products are inorganic phosphate and adenyl-5-yl phosphoramidate (AMP-PN) as determined by HPLC analysis. The hydrolysis occurs in both the presence and absence of added divalent metal ions and is stimulated by potassium. The kinetic properties of the hydrolytic reaction depend markedly on the identity of the added divalent metal. GMP-PNP and AMP-CPP are also hydrolyzed, while AMP-PCP is not. Adenyl-5-yl phosphoramidate is a potent effect of beef heart mitochondrial ATPase activity. Based on these data, a reinterpretation of work based on the assumption that AMP-PNP is not hydrolyzed is presented.
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PMID:Hydrolysis of adenyl-5-yl imidodiphosphate by beef heart mitochondrial ATPase. 286 12

Based on commonalities between peripheral blood "immunocytes" and central nervous system cells (both have receptors for endorphins, enkephalins, dopamine, acetylcholine, etc.) blocking of potassium ion channels in both brain cell synaptosome and suppressor T cells, and common sharing of antigenic determinants on one or another immunocyte and one or another CNS cells, we postulated that peripheral blood immunocytes can be used to study CNS mechanisms. In the present studies we used peripheral blood lymphocytes to study the effects of phencyclidine (PCP) on various receptors. This agent causes a permanent psychosis similar to chronic schizophrenia in a small percent of users. We observed similar effects in binding to sigma receptors, inhibition of binding and reversibility of binding in receptors of both human peripheral blood receptors and the mouse neuroblastoma, a hamster brain cell hybrid clone. The results are complete with the hypothesis that some cases of schizophrenia are immunologically mediated, perhaps due to antibodies to the sigma receptor. Alternatively, immunologic deficiency might hinder elimination of neurotropic viruses which in genetically predisposed individuals bind to and block the sigma receptor. Functional deficiency of the brain cell equivalent of lymphocyte suppressor T cells by one or another immunologic mechanisms or an excess of T helper cells might also cause schizophrenia by causing an excess of normal brain "B-cell equivalent cell" output response to sensory input.
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PMID:Sigma receptors and autoimmune mechanisms in schizophrenia: preliminary findings and hypotheses. 609 18

The effect of phencyclidine (PCP) on the release and synthesis of [3H]-dopamine ( [3H]-DA) newly synthesized from [3,5-3H]-L-tyrosine was studied under both basal and potassium-stimulated conditions in slices from the rat striatum. Phencyclidine (3-100 microM) stimulated the release of [3H]-DA during superfusion with low level potassium (4.5 mM) buffer, but had no effect on the release of [3H]-DA elicited by superfusion with buffer containing 40 mM potassium. On the other hand, phencyclidine had no effect (except at 100 microm) on the spontaneous release of [3H]-H2O (formed as a result of the hydroxylation of [3,5-3H]-L-tyrosine), but inhibited the increase in formation of [3H]-H2O normally associated with potassium-induced depolarization. These data are discussed in relation to results obtained with phencyclidine on other in vitro and in vivo models of dopaminergic function.
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PMID:Effects of phencyclidine on the release and synthesis of newly formed dopamine. 613 82

Mouse lymphoma cells were shown to be unresponsive to prostaglandin E1 in terms of cAMP production. The endogenous ATP concentration was shown to be low. Addition of ATP in the presence of IMBX into the incubation medium resulted in elevation of the intracellular pool of ATP and the cells responded to PGE1 by increasing cAMP production. The ATP effect is specific and cannot be substituted by GTP. ATP analogue (AMP-PCP) can, however, produce a similar effect to ATP. The intracellular ATP concentration can be lowered by incubation with iodoacetate and potassium cyanide. This caused a drastic decrease of the cAMP level. Ethionine on the other hand had no effect on the intracellular ATP level.
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PMID:ATP uptake by mouse lymphoma cells. 618 Jun 74

1. Changes in the intrinsic fluorescence of Na, K-ATPase protein have been used to monitor the interconversion of E(1) (low fluorescence) and E(2) (high fluorescence) forms of the unphosphorylated enzyme.2. In media lacking sodium and nucleotides, 1 mM-potassium was sufficient to convert practically all of the enzyme into the E(2) form. In media containing 1 mM-potassium, 1 mM-EDTA, and no sodium or magnesium, the addition of ATP, or its beta, gamma-imido or methylene analogues, converted the enzyme back into the E(1) form. The relation between nucleotide concentration and the fraction of the enzyme that was in the E(1) form could be described by a rectangular hyperbola, with a K((1/2)) of about 15 muM for ATP, 65 muM for adenylyl-imidodiphosphate (AMP-PNP) and 180 muM for adenylyl (beta, gamma-methylene)-diphosphonate (AMP-PCP). ADP also converted the enzyme back into the E(1) form, with a K((1/2)) of about 25 muM, but the relation between concentration and fraction converted was not well described by a rectangular hyperbola.3. In similar media containing 50 mM-potassium, much higher concentrations of ATP were required to convert the enzyme back into the E(1) form, and the conversion was probably incomplete.4. If we assume that ATP and potassium ions affect each other's binding solely by altering the equilibrium between E(1) and E(2) forms of the enzyme, we are able to conclude (i) that potassium ions bind to the E(1) form with a moderately low affinity, (ii) that, in the absence of nucleotides, the equilibrium between E(1)K and E(2)K is poised strongly in favour of E(2)K, (iii) that the binding of ATP to a low-affinity site alters the equilibrium constant for the interconversion of E(1)K and E(2)K by two to three orders of magnitude, so that, at saturating levels of ATP, the equilibrium is probably slightly in favour of E(1)K, and (iv) that in sodium-free, potassium-containing media, ATP will appear to bind to the enzyme more tightly than would be expected from the dissociation constant of the E(2)K. ATP complex.5. The pattern of the equilibrium constants for the various reactions between E(1), E(2), ATP and potassium is compatible with the hypothesis that the ATP-accelerated conversion of E(2)K into E(1)K, and the subsequent release of potassium ions from low-affinity inward-facing sites, are part of the normal sequence of events during potassium influx in physiological conditions.
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PMID:The equilibrium between different conformations of the unphosphorylated sodium pump: effects of ATP and of potassium ions, and their relevance to potassium transport. 624 81

A major approach to the elucidation of the mechanisms by which phencyclidine (PCP) elicits the varied and complex responses observed in biological systems consists of comparisons of the pharmacological profiles of PCP derivatives with those of drugs for which the mechanism of action is better understood. Such studies depend on the definition of discriminant structure-activity relationships and on comparisons of rank orders of potency for the actions of PCP derivatives. Using the muscarinic cholinergic system in brain and the potassium ion channels in cardiac muscle as targets for PCP derivatives, we review the elucidation of the structural determinants for PCP recognition at muscarinic receptors, and the dramatic effect of assay conditions on the rank order of potency for the action of PCP derivatives at intracellular sites. The structural and physicochemical considerations illustrated here must be considered basic to the establishment of any assay aimed at the elucidation of the mechanism of action of PCP.
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PMID:Multiple actions of phencyclidine: discriminant structure-activity relationships from molecular conformations and assay conditions. 630 61

Phencyclidine ("PCP" or "angel dust") and some of its derivatives are psychotomimetic drugs that have been used in general anesthesia for some time. This drug blocks potassium ion channels in brain tissue, and there is a specific PCP binding to lymphocytes. In a study of the effects of this drug on immunocyte function, it was found that humoral and cellular immune responses in vitro were depressed when immunocytes were treated with PCP before biological assay. This finding has implications for PCP abuse and also for the use of its derivative in general anesthesia, where it may contribute to postoperative infection.
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PMID:Phencyclidine-induced immunodepression. 632 64

The effects of phencyclidine [1-(1-phenylcyclohexyl)-piperidine; PCP] on cardiac action potential duration (APD) were compared to those of some of its derivatives, in strips of isolated frog ventricular muscle perfused with normal Ringer solution. We studied compounds with PCP-like behavioral actions (N-ethyl-1-phenyl-cyclohexylamine: PCE; and m-amino-PCP) as well as behaviorally inactive analogs (m-nitro-PCP; the quaternary derivative PCP-methyl iodide; and various fragments of the PCP molecule). Exposure to PCP, 3 microM to 1 mM, produced reversible, dose- and pH-dependent prolongations, of the APD to over 100% above control. The observed effects of the drugs are compatible with a mechanism of blockade of potassium conductance. An intracellular site for this action is suggested by: (i) the inactivity of the quaternary analog; (ii) the marked increase in the potency of the compounds when the external pH is changed in the region of their respective pKa values to increase the concentration of the unionized species; and (iii) the pronounced acceleration of the termination of the PCP effect by washout with a series of buffer solutions with decreasing pH values. The rank order of potency of the compounds in lengthening APD (PCE greater than m-amino PCP greater than PCP much much greater than m-nitro-PCP) is the same as reported from other pharmacological studies of specific PCP actions, and matches the rank of behavioral activity of the drugs.
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PMID:Effects of phencyclidine on cardiac action potential: pH dependence and structure-activity relationships. 660 10

Activation of the sympathetic system by phencyclidine (PCP) should result in catecholamine release from the adrenals. However, adrenalectomy does not reduce PCP-induced hypertension. In an attempt to rectify this inconsistency, the direct effects of PCP on the bovine adrenal medulla were examined. At (3 X 10(-6) M), PCP reduced the acetylcholine-(ACh)-induced catecholamine release by 50%. Surprisingly, barium-induced secretion of catecholamines was also reduced by PCP. ACh-induced catecholamine release was not altered by 10(-3)M 4-aminopyridine (4 AP), the potassium channel blocker. Thus, calcium antagonist actions of PCP and consequent block of catecholamine secretion from adrenal medulla may explain the lack of effect of adrenalectomy on PCP-induced hypertension. Possible contributions of calcium and/or potassium channel blockade to other manifestations of PCP overdosage are discussed.
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PMID:Block by phencyclidine of acetylcholine and barium induced adrenal catecholamine secretion. 688 80


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