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 specific binding of [3H]TCP and [3H](+)3-PPP, radioligands which respectively label PCP-NMDA and sigma binding sites was measured in tissue homogenates prepared from dissected areas of control and schizophrenic postmortem brains. [3H]TCP binding was bilaterally increased in orbital frontal cortex (Brodmann area 11) of schizophrenic brains. This finding may be due to an increased glutamatergic innervation of orbital frontal cortex since it parallels our findings of increased [3H]kainate and [3H]D-aspartate binding in this area. In contrast, [3H](+)3-PPP binding was reduced in each of the four brain regions examined. The reductions were greatest in brains from the schizophrenic subjects receiving neuroleptics at the time of death. Neuroleptics remaining in the brains of these subjects may compete in vitro with [3H](+)3-PPP for binding to the sigma site.
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PMID:Alterations in phencyclidine and sigma binding sites in schizophrenic brains. Effects of disease process and neuroleptic medication. 168 83

The interaction of several sigma and PCP receptor ligands with the norepinephrine uptake carrier was investigated in the rat tail artery and brain. These ligands include haloperidol; (+)- and (-) 3-(3-hydroxy- phenyl)-N-(1-propyl)piperidine (3-PPP), (+/-)-BMY 14802, [(+/-) alpha-(4-fluoro- phenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol]; (+)-SKF 10047, [(+/-)-N-allyl-N-normetazocine]; 1,3-di-ortho-tolyl-guanidine; rimcazole (BW 234U), [cis-9-[3-(3,5-dimethyl-1-piperazinyl)propyl] carbazole dihydrochloride]; and MK 801, [(+)-5-methyl-10,1 1-dihydro-5H-dibenzo[a, d]cyclohepten-5, 10-imine maleate]. Our results show that all ligands used, except 1,3-di-ortho-tolyl-guanidine, inhibit both neuronal [3H]norepinephrine accumulation in the rat tail artery and specific [3H] desmethylimipramine binding in the rat brain. Except for (+)-SKF 10047, the order of potency of the ligands used for inhibiting neuronal [3H]norepinephrine accumulation in the rat tail artery was similar to that measured for inhibition of specific [3H]desmethylimipramine binding in the rat brain. Despite these similarities, our results also suggest that haloperidol, (+)- and (-)3-PPP, MK 801, rimcazole and cocaine interact with the [3H]norepinephrine site in the rat tail artery and with the [3H]desmethylimipramine binding site in the rat brain in a complex fashion. These studies demonstrate an important action on the norepinephrine carrier by these sigma and PCP ligands in the rat tail artery and brain.
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PMID:Interactions of sigma and phencyclidine receptor ligands with the norepinephrine uptake carrier in both rat brain and rat tail artery. 184 98

Most agents employed for the investigation of sigma (sigma) binding sites display relatively low affinity for these sites, bind both at sigma sites and at either phencyclidine (PCP) sites or dopamine receptors with similar affinity, and/or produce some dopaminergic activity in vivo. We describe a new agent, (-)PPAP or R(-)-N-(3-phenyl-n-propyl)-1-phenyl-2-aminopropane hydrochloride, that binds with high affinity and selectivity at sigma (IC50 = 24 nM) versus either PCP sites (IC50 greater than 75,000 nM) or D1 and D2 dopamine receptors (IC50 greater than 5,000 nM). The sigma affinity of this agent is comparable to that of the standard ligands (+)-3-PPP and DTG. Furthermore, although (-)PPAP is structurally related to amphetamine, it neither produces nor antagonizes amphetamine-like stimulus effect in rats trained to discriminate 1 mg/kg of S(+)amphetamine from saline.
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PMID:(-)PPAP: a new and selective ligand for sigma binding sites. 196 44

Haloperidol and (+)-3-PPP, compounds with known affinity for the sigma-receptor, have been examined for their ability to reduce the excitatory actions of N-methyl-DL-aspartate (NMDLA), quisqualate and kainate on rat spinal neurons in-vivo. The actions of (-)-3-PPP were also tested. Haloperidol was injected intravenously whereas the 3-PPP enantiomers were administered by microelectrophoresis. Haloperidol had little effect on excitations evoked by NMDLA, quisqualate or kainate whereas both (+)- and (-)-3-PPP usually enhanced, non-selectively, responses to all three excitatory amino acid analogues. The results support suggestions that phencyclidine (PCP)-like compounds with affinity for both PCP and sigma-receptors reduce neuronal excitations mediated by the N-methyl-D-aspartate (NMDA) receptor via a selective effect at the PCP site.
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PMID:Failure of sigma-receptor ligands to reduce the excitatory actions of N-methyl-DL-aspartate on rat spinal neurons in-vivo. 196 52

The active site of minaprine (3-(2-morpholinoethylamino)-4-methyl-6-phenylpyridazine) was studied by means of receptor binding and its effect on acetylcholine (ACh) release in rat hippocampus. [3H]Minaprine binding to the hippocampal membrane was inhibited by minaprine, 4-aminopyridine (4-AP) and phencyclidine (PCP) dose-dependently, whereas it was not inhibited by L-glutamate (L-Glu), N-methyl-D-aspartate (NMDA), 2-amino-5-phosphonovalerate (APV), 3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)3-PPP) or ketamine. [3H]PCP binding was inhibited by PCP and APV in an extensively washed hippocampal membrane. Minaprine, however, failed to inhibit the [3H]PCP binding. [3H]3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) binding was inhibited by L-Glu but not by minaprine. NMDA-evoked [3H]ACh release from the rat hippocampal slices was effectively inhibited by PCP. However, minaprine had no effect on the NMDA-evoked [3H]ACh release. Similar results were obtained from the study of [3H]ACh release in the striatum. These results suggest that minaprine exerts its action via the voltage-dependent K+ channel but not via the NMDA receptor-channel complex or sigma receptor.
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PMID:Differentiation of the active site of minaprine from that of phencyclidine in rat hippocampus. 197 91

SKF 10,047 (N-allylnormetazocine) was found to be neuroprotective against glutamate-induced excitotoxicity in our model system of energy-stressed neurons which rapidly succumb to glutamate via N-methyl-D-aspartate (NMDA) receptor-mediated events. The 50% protective concentration (PC50) of the (+) and (-) enantiomers was 3.3 microM and 9 microM, respectively, against the toxic action of 100 microM glutamate. Protection by SKF 10,047 seemed to be mediated by the lower-affinity phencyclidine (PCP) binding site rather than the higher-affinity sigma-site since the potent sigma-ligand (+)-3-(3-hydroxyphenyl-N-1-propyl)piperidine [+)-3-PPP) did not protect at concentrations up to 2 mM. A reversed stereoselectivity was apparent for neuroprotection since (-)-3-PPP was weakly protective with a PC50 of 1.5 mM. These data suggest that energy-stressed rat cerebellar granule cells are a useful model for identifying neuroprotective agents, as shown by SKF 10,047.
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PMID:Excitatory amino acid neurotoxicity at the N-methyl-D-aspartate receptor in cultured neurons: protection by SKF 10,047. 198 87

Scratching induced by intrathecal (IT) administration of kainic acid (0.5 nmol) to rats was inhibited by IT pretreatment with the selective mu agonists levorphanol (30 and 90 nmol), [D-Ala2,N-Met-Phe4,Gly5-ol]-enkephalin (DAGO, 0.4 and 1.1 nmol), or morphine (90 nmol), the mixed mu-delta agonist [D-Ala2,D-Leu5]-enkephalinamide (DADLE, 10 and 30 nmol), or the sigma/phenycyclidine (PCP) agonists dextrorphan (90 nmol) or (+)-N-allyl-N-normetazocine ([+]-NAM, 90 nmol). The kappa agonists dynorphin (1.1 nmol) and ethylketocyclazocine (EKC, 90 nmol) had no significant effect, nor did the selective delta agonist [D-Pen2,D-Pen5]-enkephalinamide (DPDPE, 90 nmol). The nonopioids (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ([+]-3-PPP, 90 nmol) and PCP (90 nmol), selective for sigma and PCP sites, respectively, both antagonized kainic-induced scratching. Levorphanol- and DADLE-induced attenuation of scratching was partially antagonized by naltrexone. These findings suggest that opioid inhibition of kainic acid-induced scratching is mediated by classical mu receptors as well as sigma and PCP sites.
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PMID:Opioid inhibition of kainic acid-induced scratching: mediation by mu and sigma but not delta and kappa receptors. 215 73

The functional effects of sigma and PCP receptor ligands were examined in the perfused rat tail artery. The following ligands were studied: haloperidol; (+)-3-PPP [(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine]; (+-)-BMY 14802 [(+-)-alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol]; DTG [1,3-di-orthotolyl-guanidine]; rimcazole (BW 234U) [cis-9-[3-(3,5-dimethyl-1-piperazinyl)propyl]carbazole dihydrochloride]; (+)-SKF 10047 [(+)-N-allyl-N-normetazocine]; TCP, [1-[1-(2-thienyl)cyclohexyl] piperidine]; and MK 801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate]. (+)-3-PPP, (+)-SKF 10047, MK 801 and TCP potentiated contractile responses to norepinephrine, an effect which was blocked by cocaine implying an action of these agents on monoamine uptake. In the presence of cocaine an additional postjunctional inhibitory action of (+)-3-PPP and (+)SKF 10047 on norepinephrine-induced contractile responses was unveiled. In contrast, haloperidol, (+/-)-BMY 14802, rimcazole and DTG inhibited contractile responses to norepinephrine. Haloperidol, (+/-)-BMY 14802 and (+)-SKF 10047 (+ uptake blockade) also inhibited contractile responses to serotonin. The order of potency for inhibition of norepinephrine-induced contractions was haloperidol greater than (+/-)-BMY 14802 greater than (+)-3-PPP greater than rimcazole greater than (+)-SKF 10047 (+ uptake blockade) greater than DTG. These studies demonstrate the lack of selectivity of many sigma and PCP ligands, significant effects on norepinephrine uptake, as well as the potential utility of the rat tail artery to explore the functional properties of these ligands.
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PMID:Multiple vascular effects of sigma and PCP ligands: inhibition of amine uptake and contractile responses. 215 42

Several phencyclidine (PCP) and sigma receptor ligands were examined for their effects on a single trial passive avoidance test in rats. Rats were administered the PCP receptor ligands (+)-5-methyl-10,11-dihydro-5Hdibenzo[a,d]cyclohepten-5,10-im ine maleate (MK-801), PCP, ketamine or the sigma receptor ligands (+)-N-allylnormetazocine ((+)-NANM), (+)-pentazocine, (+)-3-(3-hydroxyphenyl)-N-n-propylpiperidine ((+)-3-PPP) or 1,3-Di(2-[5-3H]tolyl)guanidine (DTG) subcutaneously prior to acquisition of the passive avoidance response, and tested 24 h later for retention. MK-801 (0.1-0.3 mg/kg), PCP (0.54-1.7 mg/kg), ketamine (10.0-17.2 mg/kg) and (+)-N-allylnormetazocine (5.4-10.0 mg/kg) produced significant memory deficits. (+)-Pentazocine (54 mg/kg) and (+)-3-PPP (30 mg/kg) also produced retention deficits, but at significantly higher doses. DTG (0.3-3.0 mg/kg s.c.) had no effect on retention. There was a positive correlation between production of retention deficits and the compounds' PCP receptor binding affinity. The results suggest that the sigma receptor is not involved in learning the passive avoidance response.
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PMID:Differential effects of sigma and phencyclidine receptor ligands on learning. 216 53

Potassium-evoked release of cholecystokinin (CCK) from slices of caudate-putamen, hippocampus, and cerebral cortex was inhibited in a dose-related fashion by phencyclidine (PCP). In order to further examine this effect, PCP-like ligands (dexoxadrol, levoxadrol, PCMP and MK-801) as well as compounds known to interact with the sigma receptor ((+)-SKF, DTG, (+)-3-PPP, and pentazocine) were tested. While some of these compounds inhibited CCK release, their rank order potency (Dex = Lev greater than PCP = PCMP greater than DTG = MK-801 = (+)-3-PPP) differs from that of known PCP-N-methyl-D-aspartate linked effects or sigma interactions. These results suggest that the mechanism by which PCP acts to inhibit CCK release may involve a novel type of PCP interaction.
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PMID:Inhibition of potassium-evoked release of cholecystokinin from rat caudate-putamen, cerebral cortex and hippocampus incubated in vitro by phencyclidine and related compounds. 217 16


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