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)

1. Rat brain synaptosomes and cultured bovine adrenal chromaffin cells were used to monitor the inhibitory effects of phencyclidine (PCP) and sigma (sigma)-receptor ligands on the uptake of [3H]-noradrenaline ([3H]-NA). 2. A Na(+)-dependent high affinity uptake was observed in synaptosomes (30 degrees C) and chromaffin cells (37 degrees C) with Km of 0.22 and 0.56 microM and Vmax of 2.5 pmol min-1 mg-1 protein and 0.7 pmol min-1 per 10(6) cells, respectively. 3. PCP and haloperidol inhibited the high affinity uptake with IC50 of 0.17 and 0.42 microM, respectively in synaptosomes and 0.24 and 0.47 microM, respectively in adrenal chromaffin cells. 4. A close correlation (r = 0.96) was established between the ability of various PCP and sigma-receptor ligands to inhibit [3H]-NA uptake in both systems: PCP greater than TCP greater than haloperidol greater than 3-(+)-PPP greater than MK-801 greater than or equal to (-)-butaclamol greater than (+)-SKF-10047 greater than DTG. Spiperone and opioid receptor ligands were ineffective at 20 microM. 5. These results indicate that the central and peripheral inhibitory effects of PCP and sigma-receptor ligands on [3H]-NA uptake involves a receptor (sigma 1-like) which is distinct from that (PCP2) recognized for the inhibition of [3H]-dopamine uptake by PCP.
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PMID:Role of the sigma receptor in the inhibition of [3H]-noradrenaline uptake in brain synaptosomes and adrenal chromaffin cells. 165 47

The (-)- and (+)-isomers of the cis- and trans-Ph/Me 1-(1-phenyl-2-methylcyclohexyl)piperidines have been synthesized and the achiral cis- and trans-Ph/Me 1-(1-phenyl-4-methylcyclohexyl)piperidines were prepared, and their in vitro [displacement of [3H]TCP (1-[1-(2-thienylcyclohexyl)]piperidine) from the PCP (1-(1-phenylcyclohexyl)piperidine) binding site] and in vivo (rotarod assay) activities determined. The 1-(1-phenyl-2-methylcyclohexyl)piperidine isomers were resolved by classical crystallization procedures, through the diastereomeric salts obtained with d- and l-10-camphorsulfonic acid. The relative stereochemistry of the cis- and trans-Ph/Me 1-(1-phenyl-2-methylcyclohexyl)piperidines and the achiral cis- and trans-Ph/Me 1-(1-phenyl-4-methylcyclohexyl)piperidines was established by using 13C and 1H NMR. Both (-)-trans-1-(1-phenyl-2-methylcyclohexyl)piperidine ((-)-2) and (+)-trans-1-(1-phenyl-2-methylcyclohexyl)piperidine ((+)-2) were examined by single-crystal X-ray analysis, and the absolute configuration of (-)-2 was determined to be 1S,2R. The (-)-2 was found to be about five times more potent than PCP in vitro and twice as potent in vivo. It is the most potent of all of the simple methyl-substituted cyclohexyl PCP isomers and is among the most potent PCP-like compounds which have been synthesized. It was nine times more potent in vitro and four times more potent in vivo than (+)-2. The racemic cis-1-(1-phenyl-2-methylcyclohexyl)piperidine (3), and its enantiomers ((+)-3 and (-)-3), were essentially inactive in vitro and in vivo. The cis-Ph/Me 1-(1-phenyl-4-methylcyclohexyl)piperidine (18) was more potent than trans-Ph/Me 1-(1-phenyl-4-methylcyclohexyl)piperidine (17), but considerably less potent than (-)-2. The enantioselectivity observed at the PCP binding site for (-)-2 could indicate that this site can discriminate between enantiotopic edges of the achiral PCP (choosing the pro-1-S edge), as does the mu-opioid receptor in the prodine series of opioids. Benzimidoyl or benzoyl group replacement of the phenyl ring in the 1-(1-phenyl-2-methylcyclohexyl)piperidine series gave compounds which showed little in vitro and in vivo activity.
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PMID:Synthesis, stereochemistry, and biological activity of the 1-(1-phenyl-2-methylcyclohexyl)piperidines and the 1-(1-phenyl-4-methylcyclohexyl)piperidines. Absolute configuration of the potent trans-(-)-1-(1-phenyl-2-methylcyclohexyl)piperidine. 187 52

The enantiomers in the alpha and beta series of cyclazocine were evaluated for their ability to bind to phencyclidine (PCP) and mu-opioid receptors in order to determine their receptor selectivity. The affinity of (-)-beta-cyclazocine for the PCP receptor was 1.5 greater than PCP itself. In contrast, (-)-alpha-cyclazocine, (+)-alpha-cyclazocine, and (+)-beta-cyclazocine were 3-, 5- and 138-fold less potent than PCP, respectively. Scatchard analysis of saturable binding of [3H]Tyr-D-Ala-Gly-N-MePhe-Gly-ol (DAMGO) also exhibited a homogeneous population of binding sites with an apparent KD of 1.9 nM and an estimated Bmax of 117 pM. [3H]Tyr-D-Ala-Gly-N-MePhe-Gly-ol (DAMGO) binding studies revealed that (-)-alpha-cyclazocine (KD = 0.48 nM) was 31-, 1020- and 12,600-fold more potent than (-)-beta-cyclazocine, (+)-alpha-cyclazocine and (+)-beta-cyclazocine, respectively, for binding to the mu-opioid receptor. These data show that, although (-)-beta-cyclazocine is a potent PCP receptor ligand consistent with its potent PCP-like discriminative stimulus effects, it shows little selectivity for PCP receptors since it also potently displaces mu-opioid binding. However, these cyclazocine isomers, due to their extraordinary degree of stereoselectivity, may be useful in characterizing the structural requirements for benzomorphans having activity at the PCP receptor.
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PMID:Affinity of the enantiomers of alpha- and beta-cyclazocine for binding to the phencyclidine and mu opioid receptors. 215 22

1. CI-977 is a new, nonpeptide kappa-opioid compound that has been synthesized and its pharmacological properties determined in a series of in vitro and in vivo rodent models. 2. In a radioligand binding studies, with guinea-pig forebrain homogenates, CI-977 bound with high affinity to [3H]-U69593-labelled kappa-sites (Ki = 0.11 nM) but with low affinity to [3H]-[D-Ala2, MePhe4, Gly-ol5] enkephalin (DAMGO) labelled mu-sites (Ki = 99 nM) and [3H]-[D-Pen2.5]enkephalin (DPDPE) labelled delta-sites (Ki = 1.04 microM). CI-977 also bound with negligible affinity to [3H]-(+)-3-(1-propyl-3-piperi-dinyl)phenol (3-PPP) labelled sigma-sites (Ki = 1.9 microM) and [3H]-1-(1-[2-thienyl]cyclohexyl)piperidine (TCP) labelled PCP sites (Ki greater than 10 microM). 3. CI-977 produced a potent inhibition of the electrically-evoked contractions of the guinea-pig ileum and rabbit vas deferens with IC50 values of 0.087 nM and 3.3 nM, respectively. The pKB values for the opioid antagonists naloxone (7.6) and norbinaltorphimine (10.5) supported the kappa nature of the CI-977-mediated effects in the smooth muscle assays. 4. CI-977 was a potent antinociceptive agent against a mechanical noxious stimulus in rats following intravenous, intramuscular, subcutaneous and oral administration. CI-977 was also effective against mechanical and chemical noxious stimuli in the mouse but ineffective against a thermal stimulus. The antinociceptive effects produced by CI-977 were completely reversed by naloxone (1 mg kg-1, s.c.). 5. At doses close to those required to produce antinociception, CI-977 also caused a naloxone-reversible diuresis and inhibition of locomotor activity.6. The in vitro and in vivo pharmacological profile of CI-977 demonstrates that it is a potent and selective agonist at the Kappa-opioid receptor.
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PMID:CI-977, a novel and selective agonist for the kappa-opioid receptor. 217 14

It has recently been demonstrated that morphine produces a loss of hepatocellular glutathione in mice by virtue of its action within the central nervous system. The ability of opioid receptor antagonists to abolish morphine's effect on hepatic glutathione suggests that this action is opioid-receptor mediated. The involvement of opioid receptors in this phenomenon is confirmed in the present study in mice by the ability of naltrexone, 100 micrograms administered intracerebroventricularly (i.c.v.), to completely block the decrease in hepatic glutathione induced by an i.c.v. injection of 100 micrograms of morphine. Intracerebroventricular administration of the selective mu (mu) opioid receptor agonist, (D-Ala2,N-MePhe4,Gly-ol5)enkephalin (DAGO; 25-50 micrograms), or the selective delta (delta) opioid agonist, [D-Pen2,D-Pen5]enkephalin (DPDPE; 3-50 micrograms), like morphine, produced significant decreases in hepatic glutathione 3 h after administration. The selective kappa (kappa) opioid receptor agonists, ethylketocyclazocine (1-30 micrograms) and trans-(+/-)3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide-methane sulfonate (U50 488; 10-300 micrograms), as well as the selective sigma (sigma) opioid agonists, phencyclidine (PCP; 50-300 micrograms) and N-allylnormetazocine (SKF 10,047; 1-30 micrograms), had no effect on the concentrations of glutathione in the liver. It appears from these data that stimulation of mu- or delta-, but not kappa- or sigma-opioid receptors within the central nervous system results in a loss of hepatocellular glutathione.
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PMID:Centrally mediated opioid induced depression of hepatic glutathione: effects of intracerebroventricular administration of mu, kappa, sigma and delta agonists. 284 4

The profile of action of eptazocine, a novel analgesic, on opioid receptors was investigated. Eptazocine caused a concentration-dependent inhibition against the [3H]-naloxone [( 3H]-NLX) specific binding to rat brain synaptic membrane in the absence of sodium cation and GTP (IC50; 7.83 +/- 1.57 microM). The ratios of IC50 values between the absence to the presence of sodium cation alone or sodium cation and GTP were 3.89 and 4.35, respectively. In addition, eptazocine (10 microM) also produced the significant decrease of [3H]-NLX specific binding in the mouse brain synaptic membrane. Moreover, the same dose eptazocine significantly decreased the [3H]-ethylketocyclazocine [( 3H]EKC) specific binding, but not [3H]-phencyclidine [( 3H]-PCP). These results suggest that eptazocine interacts with opioid receptor, and is classified as one of the opiate agonist-antagonist analgesics.
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PMID:The interaction of eptazocine, a novel analgesic, with opioid receptors. 299 58

We investigated the effects of N-allylnormetazocine (SKF 10,047) and morphine on the stereotyped behaviors induced by the intraperitoneal injection of phencyclidine (PCP). PCP-induced turning and backpedalling were significantly potentiated by pretreatment with SKF 10,047 (10 mg/kg) but sniffing and head weaving were not. On the other hand, pretreatment with morphine dose-dependently attenuated PCP-induced sniffing and head weaving, but not turning and backpedalling. These results suggest that PCP-induced stereotypy may be mediated by not only a sigma opioid receptor but also some other receptors. In addition, each component of PCP-induced stereotypy may be controlled by different opioid systems and/or neuronal systems.
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PMID:Phencyclidine-induced stereotyped behaviors after injection of morphine and N-allylnormetazocine (SKF 10,047) in rats. 301 58

This study was performed to characterize pharmacologically the discriminative stimulus effects of dextromethorphan, an antitussive that binds with high affinity to a subtype of sigma site in the brain. Dextrorphan, a metabolite of dextromethorphan, has phencyclidine (PCP)-like effects. Therefore, training was conducted with dextromethorphan injected by the SC route, which minimizes dextrorphan formation compared to the IP route. The training dose used, 30 mg/kg, by the SC route did not occasion selection of the PCP-appropriate choice lever in rats discriminating IP injections of 2.0 mg/kg PCP from saline. (In contrast, by the IP route the ED50 of dextromethorphan for PCP-appropriate lever selection was 21.7 mg/kg). In rats discriminating 30 mg/kg (SC) of dextromethorphan from distilled water, dextromethorphan was slightly more potent SC than it was IP (ED50s for dextromethorphan-appropriate lever selection: 8.5 and 14.9 mg/kg, respectively). These animals generalized dose-dependently and completely to PCP and to other PCP-receptor ligands, but selected the vehicle-appropriate choice lever when tested with sigma-site ligands, mu-opioid agonists, and naltrexone. Concurrent administration of naltrexone or sigma-site ligands with 30 mg/kg dextromethorphan did not block dextromethorphan-appropriate responding. These results show that the discriminative effects of SC dextromethorphan are PCP-like and are not mediated by the high-affinity dextromethorphan binding site or by the mu-opioid receptor. Because little dextrorphan is formed when dextromethorphan is given SC and because dextromethorphan itself has low affinity for the PCP receptor, the discriminative effects of SC dextromethorphan probably are mediated by a recognition site related closely to but different from the PCP receptor.
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PMID:Discriminative stimulus effects of dextromethorphan in the rat. 789 13

N-allylnormetazocine (SKF-10047) and related benzomorphans induce psychotomimetic effects in animals and humans, and bind a unique, non-opioid receptor, denoted the sigma site. Sigma receptors have been found in the cortical and limbic structures in human postmortem brain: their anatomical distribution is different from phencyclidine (PCP) sites. Sigma receptors regulate not only dopamine, excitatory amino acid and PCP receptors, but also interact neuropeptides. Endogenous sigma ligands are not yet determined. Isolation and cloning of the receptor genes have not yet been successful. Selective loss of cerebral cortical sigma, but not PCP binding sites, has been observed in schizophrenia. A more compelling role for sigma sites in schizophrenia is indicated by the high affinity of some neuroleptic drugs, including haloperidol, for sigma sites. Rimcazole, a weak but selective sigma ligand, has very good clinical efficacy as a neuroleptic agent and has few side effects. Thus, sigma ligands may be useful in the treatment of schizophrenia. The present review describes properties of sigma receptors and its roles in relation to sigma ligands in the regulation of the central nervous system on the basis of the results of more recent studies.
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PMID:[Physiological function of sigma receptors: central pharmacological effects of sigma ligands]. 804 46

The role of nucleoside diphosphate kinase (NDKP), which converts GDP to GTP, in the coupling of mu-opioid receptors to G protein was investigated in membranes of Chinese hamster ovary cells stably transfected with the cloned rat mu-opioid receptor (rmor). Endogenous NDPK activity in membranes was determined to be 0.60+/-0.02 micromol/mg protein/30 min UDP (at 10 mM), a competitive substrate of NDPK for GDP with no effect on guanine nucleotide binding to G proteins, reduced basal [35S]GTPgammaS binding and unmasked morphine-stimulated [35S]GTPgammaS binding to pertussis toxin-sensitive G proteins, indicating that [35S]GTPgammaS binding to NDPK accounts for part of its high basal binding. UDP increased the extent of morphine-induced increase in [35S]GTPgammaS binding in the presence of GDP, most likely by reducing basal binding and inhibiting conversion of GDP to GTP. ATP greatly reduced morphine-induced increase in [35S]GTPgammaS binding, whereas AMP-PCP (adenylyl-(beta,gamma-methylene)-diphosphoate tetralithium salt), which cannot serve as the phosphate donor for NDPK, did not, demonstrating that effects of ATP is mediated by the NDPK product GTP. In addition, GDP and ATP increased the Kd and lowered the Bmax of the agonist [3H]DAMGO ([D-Ala2,N-Me-Phe4,Gly5ol]-Enkephalin) for the mu-opioid receptor and GDP alone increased Kd, most likely through their conversion to GTP by NDPK. Addition of exogenous NDPK enhanced the inhibitory effects of GDP and combined GDP and ATP on [3H]DAMGO binding. Thus, NDPK appears to play a role in modulating signal transduction of and agonist binding to mu-opioid receptors.
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PMID:Nucleoside diphosphate kinase associated with membranes modulates mu-opioid receptor-mediated [35S]GTPgammaS binding and agonist binding to mu-opioid receptor. 1045 35


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