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)

Receptor binding studies with [3H]-(+)SKF-10047 were carried out to characterize the putative sigma (sigma) and phencyclidine (PCP) receptors in membrane preparations of bovine adrenal medulla. Specific binding of the radiolabelled compound was observed after incubation with the membrane preparation at 37 degrees, the equilibrium being reached at 20 min and the maximal binding being observed with 0.6 mg/ml protein. Saturation binding studies were performed at equilibrium (30 min at 37 degrees with 0.5 mg/ml of membrane protein) in the presence of haloperidol (1 microM) or 1-[1-(2-thienyl) cyclohexyl] piperidine (TCP; 0.2 microM) to block sigma or PCP receptors, respectively. The binding of [3H]-(+)SKF-10047 was characterized by two distinct components. A high affinity binding site (haloperidol sensitive) had an apparent KD of 8.3 nM and a Bmax of 67 pmol/g protein. A lower affinity binding site (TCP sensitive) had an apparent KD of 32.7 nM and a Bmax of 83 pmol/g protein. The drug specificity of the high affinity binding site resembled that of the putative sigma receptor, being potently inhibited by haloperidol and pentazocine. The binding pharmacology of the low affinity site resembled that of the phencyclidine receptor, being potently displaced by TCP and PCP. The binding of [3H]-(+)SKF-10047 to both receptors showed marked stereoselectivity for the dextrorotatory (+) isomer of SKF-10047 and was insensitive to the receptor specific opioid ligands DAGO (mu), DSLET (delta) and U-69593 (kappa). These data indicate that bovine adrenal medulla contains sigma and PCP-like receptors.
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PMID:Presence of sigma and phencyclidine (PCP)-like receptors in membrane preparations of bovine adrenal medulla. 254 82

These experiments were designed to compare phencyclidine (PCP) and sigma (sigma) receptor binding sites in the rat spinal cord by using receptor binding and autoradiographic techniques. Binding sites for 3H-TCP (3H-1-[1-(2-thienyl)cyclohexy]piperidine), a PCP receptor agonist, and (+)3H-3-PPP (3H-(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine), a sigma receptor agonist, in the rat spinal cord were shown to represent two populations of recognition sites. Inhibition studies revealed that ligands with high affinity for the PCP receptor (MK-801 and PCP) were potent competitors at 3H-TCP binding sites whereas the putative sigma receptor ligands (+/-)pentazocine and haloperidol were potent competitors at (+)3H-3-PPP binding sites. The autoradiographic distribution of 3H-TCP and (+)3H-3-PPP binding sites in adjacent sections of rat spinal cord demonstrated the occurrence of two distinct populations of binding sites. 3H-TCP binding sites were localized primarily in laminae I and II in cervical and thoracic spinal segments. Binding sites in lamina I decreased in density along a rostral to caudal gradient in the spinal cord. The highest density of (+)3H-3-PPP binding sites was found in the ventral horn (lamina VIII and IX) and over perikarya in dorsal root ganglia. Significantly elevated densities of (+)3H-3-PPP binding sites were also found in lamina X within thoracic and lumbar segments and in the intermediolateral cell column. The results of the present study show that PCP and sigma receptor binding sites are differentially localized in the rat spinal cord and suggest that separate binding sites exist for PCP and sigma agonists.
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PMID:Phencyclidine and sigma receptors in rat spinal cord: binding characterization and quantitative autoradiography. 254 51

Tritium-labeled (+)-pentazocine ([3H]-1b) of specific activity 26.6 Ci/mmol was synthesized in 3 steps starting with (+)-normetazocine (2) of defined optical purity. [3H]-1b has been characterized as a highly selective ligand for labeling of sigma receptors. Competition data revealed that [3H]-1b could be displaced from guinea pig brain membrane preparations with a number of commonly used sigma receptor ligands. [3H]-1b exhibited saturable, enantioselective binding with a Kd of 5.13 +/- 0.97 nM and a Bmax of 1146 +/- 122 fmol/mg protein. Phencyclidine (PCP) displaced [3H]-1b with low affinity while MK-801 was inactive, thus indicating insignificant activity at the PCP-binding site; apomorphine failed to displace [3H]-1b indicating lack of dopamine receptor cross-reactivity. Since the affinity of [3H]-1b is about 6 times that of the two commonly employed sigma ligands ((+)-3-[3H]PPP and [3H]DTG) and since it is more selective for sigma receptors than the benzomorphan [3H]SKF-10,047, it represents the first example of a highly selective benzomorphan based sigma receptor ligand. [3H]-1b should prove useful for further study of the structure and function of sigma receptors.
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PMID:Synthesis and evaluation of optically pure [3H]-(+)-pentazocine, a highly potent and selective radioligand for sigma receptors. 256 52

Extracellular single unit recording techniques were used to study the effects of selective sigma-receptor agonist [(+)-3-PPP, (+)-pentazocine, and DTG] and selective sigma-receptor antagonists (BMY 14802 and Rimcazole) on dopamine neurons of the substantia nigra. Intravenous (IV) administration of sigma agonists decreased, whereas IV administration of the sigma antagonist BMY-14802 increased the firing rate of dopamine neurons. The other sigma antagonist Rimcazole produced inconsistent changes in dopamine unit activity. These data, in conjunction with anatomic data suggesting sigma receptor localization on dopamine neurons in the substantia nigra (Gundlach et al: J Neurosci 6:1757-1770, 1986; Graybiel et al: Soc Neurosci Abstr 13:28, 1987) demonstrate a relationship of the sigma receptor with the dopamine system and further suggest a model system to study agonist-antagonist interactions of sigma ligands. The selective phencyclidine (PCP) agonist MK-801 was equipotent to PCP in regard to stimulatory properties on dopamine neurons. However, the relative potencies do not correspond to their relative binding affinities, suggesting that non-PCP-receptor properties may mediate this effect.
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PMID:Electrophysiological effects of selective sigma-receptor agonists, antagonists, and the selective phencyclidine receptor agonist MK-801 on midbrain dopamine neurons. 257 40

The purpose of this experiment was to investigate the interaction of GABA (gamma aminobutyric acid) with PCP (phencyclidine) and sigma receptor agonists in the cerebellum. Drugs were applied directly to a single cerebellar Purkinje neuron of urethane-anesthetized rats, through a multibarrel pipette. The PCP receptor agonist, (+)PCMP [1-(-1-phenylcyclohexyl)-3-methyl piperidine], significantly enhanced GABA-induced inhibition. On the other hand, its stereoisomer, (-)PCMP, had no such modulatory effect. Dexoxadrol, a sigma receptor agonist, similar to (+)PCMP, potentiated GABA-induced depression. Its stereoisomer, levoxadrol, although inhibiting the spontaneous firings of Purkinje neurons, did not alter the effect of GABA. In conclusion, the findings indicate that the electrophysiological mechanisms of PCP-induced facilitation of GABA-induced reactions are similar to those triggered by sigma agonists in the cerebellum.
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PMID:Facilitation of gamma-aminobutyric acid-induced depression by (+)PCMP and dexoxadrol in the cerebellar Purkinje neurons of the rat. 274 47

Opioid, sigma, and phencyclidine (PCP) receptors were characterized in the mouse neuroblastoma--Chinese hamster brain hybrid cell line NCB-20. Quantitative receptor assays under equilibrium binding conditions with highly specific radioligands demonstrated the presence of delta, but not mu or kappa, opioid receptors on NCB-20 cell membranes. NCB-20 cells were shown to possess two distinct sites specific for sigma opioids and PCP derivatives. One site was labeled by (+)-[3H]N-allylnormetazocine [(+)-[3H]SKF-10,047] (Kd = 69 nM; Bmax = 4100 fmol/mg of protein). The rank order of potency of drugs at this site was (+)-3-(3-hydroxy-phenyl)-N-(1-propyl)piperidine [(+)-3-PPP] greater than haloperidol greater than (+)-SKF-10,047 greater than (+/-)-ethylketocyclazocine greater than (+/-)-bremazocine greater than N-[1-(2-thienyl) cyclohexyl]piperidine (TCP) greater than dexoxadrol. This site is similar in its ligand selectivity to the haloperidol-sensitive sigma receptor of rat brain. The other site was labeled by the potent phencyclidine derivative [3H]TCP (Kd = 335 nM; Bmax = 9300 fmol/mg of protein). This density is equivalent to approximately 60,000 sites/cell. The rank order of potency of drugs at this site was TCP greater than (+)-3-PPP greater than PCP greater than dexoxadrol greater than haloperidol greater than cyclazocine greater than levoxadrol greater than (+)-SKF-10,047; mu and delta ligands were inactive. This site is similar to the rat brain PCP receptor. The NCB-20 cell line is the only cultured cell line that has been demonstrated to have PCP receptors.
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PMID:Characterization of opioid, sigma, and phencyclidine receptors in the neuroblastoma-brain hybrid cell line NCB-20. 284 88

Computer-assisted molecular modelling techniques and electrostatic analyses of a wide range of phenycyclidine (PCP) and sigma ligands, in conjunction with radioreceptor studies, were used to determine the topographies of the PCP and sigma receptors. The PCP receptor model was defined using key molecules from the arylcyclohexylamine, benzomorphan, bridged benz[f]isoquinoline, and dibenzocycloalkenimine drug classes. Hypothetical receptor points (R1, R2) were constructed onto the aromatic ring of each compound to represent hydrophobic interactions with the receptor, along with an additional receptor point (R3) representing a hydrogen bond between the nitrogen atom and the receptor. The superimposition of these key molecules gave the coordinates of the receptor points and nitrogen defining the primary PCP pharmacophore as follows: R1 (0.00, 3.50, 0.00), R2 (0.00, -3.50, 0.00), R3 (6.66, -1.13, 0.00), and N (3.90, -1.46, -0.32). Additional analyses were used to describe secondary binding sites for an additional hydrogen bonding site and two lipophilic clefts. Similarly, the sigma receptor model was constructed from ligands of the benzomorphan, octahydrobenzo[f]quinoline, phenylpiperidine, and diphenylguanidine drug classes. Coordinates for the primary sigma pharmacophore are as follows: R1 (0.00, 3.50, 0.00), R2 (0.00, -3.50, 0.00), R3 (6.09, 2.09, 0.00), and N (4.9, -0.12, -1.25). Secondary binding sites for sigma ligands were proposed for the interaction of aromatic ring substituents and large N-substituted lipophilic groups with the receptor. The sigma receptor model differs from the PCP model in the position of nitrogen atom, direction of the nitrogen lone pair vector, and secondary sigma binding sites. This study has thus demonstrated that the differing quantitative structure-activity relationships of PCP and sigma ligands allow the definition of discrete receptors. These models may be used in conjunction with rational drug design techniques to design novel PCP and sigma ligands of high selectivity and potency.
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PMID:Receptor site topographies for phencyclidine-like and sigma drugs: predictions from quantitative conformational, electrostatic potential, and radioreceptor analyses. 284 51

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

The purpose of this study was to examine the binding and behavioral effects mediated by PCP and sigma receptors in the rat. From the radioreceptor assays, it was possible to characterize two binding sites that interact with PCP and sigma ligands. The two sites, a PCP and sigma receptor, could be differentiated based on drug selectivity and potency. In the behavioral assays, MK-801, which bound preferentially to the PCP receptor, and 1,3-di-0-tolylguanidine, which bound preferentially to the sigma receptor, induced sniffing, rearing, circling, backpedaling, and weaving behavior. These results indicate that there are distinct PCP and sigma receptors that are both involved in mediating stereotyped behavior and ataxia in the rat.
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PMID:Biochemical and behavioral effects of sigma and PCP ligands. 285 Jun 29

Phencyclidine (PCP) was examined for its ability to modulate histamine release from rat brain slices labeled with L-[3H]histidine. PCP failed to mimic but completely reversed the autoinhibitory effect of histamine at H3-receptors with an apparent Ki value of 13 +/- 3 microM. A direct interaction of PCP with H3-autoreceptors rather than PCP or sigma receptor sites was confirmed by binding studies. PCP inhibited the binding of [3H](R)alpha-methylhistamine to H3-receptor sites in rat cerebral membranes with a Ki value of 25 +/- 2 microM. It is concluded that PCP is a H3-receptor antagonist of moderate potency.
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PMID:Phencyclidine blocks histamine H3-receptors in rat brain. 285 72


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