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)

Previous work demonstrated two high-affinity PCP binding sites in guinea pig brain labeled by [3H]TCP (1-(1-[2-thienyl]cyclohexyl)piperidine): site 1 (N-methyl-D-aspartate [NMDA]-associated) and site 2 (dopamine-reuptake complex associated). The present study examined brain membranes prepared from various species, including human, for the presence of site 2, defined as binding in the presence of (+)-5-methyl-10,11-dihydro-5H-dibenzo [a, d]cyclohepten-5,10-imine maleate ((+)-MK801) minus binding in the presence of 10 microM TCP (nonspecific binding). Studies were conducted in absence of sodium which was found to be inhibitory to [3H]TCP binding. The results demonstrated detectable levels of site 2 in brain membranes of guinea pig, rabbit, pig, mouse, sheep, and human but not in the rat or chicken. Using human cortical membranes, site 2 was the predominant binding site. Detailed studies conducted with human cortical tissue showed that high-affinity dopamine (1-[2- [bis(4-fluorophenyl)-methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR12909)], [1,2]benzo(b)thiophenylcyclo-hexylpiperidine (BTCP), and serotonin (fluoxetine) uptake inhibitors produced a wash-resistant inhibition of [3H]TCP binding to site 2, but not site 1. Preincubation of guinea pig brain membranes with BTCP was shown to produce an increase in the dissociation rate of [3H]TCP from PCP site 2. Structure activity studies with various uptake inhibitors showed that GBR12909, benztropine, fluoxetine, and BTCP have higher affinity for site 2 than for site 1. (+)-MK801, ketamine, and tiletamine were very selective for site 1, whereas dexoxadrol and TCP were moderately selective for site 1. These results suggest that human cortex possesses high-affinity PCP binding sites associated with biogenic reuptake binding sites, and that guinea pig brain, but not rat brain, may be an appropriate animal model for studying PCP site 2 in human brain.
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PMID:[3H]1-[2-(2-thienyl)cyclohexyl]piperidine labels two high-affinity binding sites in human cortex: further evidence for phencyclidine binding sites associated with the biogenic amine reuptake complex. 183 49

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

Subcutaneous administration of fluphenazine elicits catelepsy that can be attenuated by the glutamate antagonists MK801 and phencyclidine (PCP). 3-[-(+)-2-carboxy piperazine-4-yl]-propyl-1-phosphanate (CPP) was found to be ineffective in this model. Intrastriatal injections of sulpiride or fluphenazine were also found to induce catalepsy which could be attenuated by MK801 and PCP. These results illustrate that nondopaminergic compounds might possibly be of value in the treatment of Parkinson's disease. Furthermore it was demonstrated that this paradigm can be utilized to investigate neurotransmitter interactions within the striatum. This was clearly emphasized by the observation that bilateral administration of MK801 into the striatum increased basal locomotor activity.
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PMID:Neuroleptic-induced catalepsy as a model of Parkinson's disease. II. Effect of glutamate antagonists. 197 10

At concentrations greater than or equal to 100 microM, phencyclidine (PCP), N-(1-(2-thienyl)-cyclohexyl)piperidine (TCP), and MK-801 induced [3H]dopamine release from dissociated cell cultures of rat mesencephalon. This release was Ca2+ independent and tetrodotoxin insensitive. Tetrodotoxin (2 microM) itself had no effect on spontaneous release of [3H]dopamine. [3H]Dopamine release was induced by 1,3-di(2-tolyl)guanidine, a sigma ligand, and by 4-aminopyridine (1-3 mM), a K+ channel blocker. No stereoselectivity was observed for [3H]dopamine release evoked by the dioxadrol enantiomers, dexoxadrol, and levoxadrol, or by enantiomers of N-allylnormetazocine (SKF 10,047). The selective dopamine uptake inhibitor 1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (GBR 12909) did not affect spontaneous or TCP-evoked [3H]dopamine release. Together, these data suggest that the dopamine-releasing effects of PCP-like compounds on the mesencephalic cells were not mediated by actions at the PCP receptor or sigma binding site, Ca2+, or Na+ channels, or at the high affinity dopamine uptake site. It remains conceivable that blocking actions of PCP-like compounds at voltage-regulated K+ channels may at least partly explain the response. These results are discussed in comparison with findings in intact brain.
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PMID:Phencyclidine and related compounds evoked [3H]dopamine release from rat mesencephalic cell cultures by a mechanism independent of the phencyclidine receptor, sigma binding site, or dopamine uptake site. 198 Apr 28

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

1. Phencyclidine (PCP) reduces the latency of rats diving into a water-filled pool from a hidden platform, without stereotyped behavior. 2. The sigma-selective ligand, NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethyl-amine monohydrochloride), attenuates the effects of PCP in this procedure. 3. The serotonin2 (5-HT2) antagonist, ritanserin, and the sigma receptor ligands, 1-(cyclopropylmethyl)-4-[2'(4"-fluorophenyl)-2'-oxoethyl]- piperidine HBr (Dup734), 4-[2'-(4"-cyanophenyl)-2'-oxoethyl]-1- (cyclopropylmethyl)piperidine (XJ448), alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol (BMY14802) and rimcazole similarly attenuate the effects of PCP. 4. The dopamine D2/sigma ligands, haloperidol and cis-N-(1-benzyl-2-methyl-pyrrolidin-3-yl)-2-methoxy-5-chloro-4- methylaminobenzamide (YM-09151-2) completely reverse the effects of PCP, whereas the same dose ranges of these drugs produce sedation. 5. The dopamine D2-selective antagonist, sulpiride, has no apparent effect on the PCP latency to the rat dive. 6. Thus, PCP-induced diving behavior was improved by sigma ligands and the 5-HT2 antagonist. This model of negative symptoms in an experimental animal will facilitate experiments on drug treatments for schizophrenia.
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PMID:The sigma-selective ligand NE-100 attenuates the effect of phencyclidine in a rat diving model. 771 58

N,N-Dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100) is a selective and potent sigma receptor ligand. We investigated the effects of NE-100 on phencyclidine (PCP)-induced cognitive dysfunction in rats in a water maze task. NE-100 significantly shortened the PCP-induced prolonged swimming latency as did 1-(cyclopropylmethyl)-4-[2'(4"-fluorophenyl)-2'-oxoethyl]- piperidine monohydrobromide (Dup 734), 4-[2'-(4"-cyanophenyl)-2'-oxoethyl]-1-(cyclopropyl-methyl)pi peridine (XJ 448), alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol (BMY 14802) and rimcazole, all of which are sigma receptor ligands and possibly antagonists. Ritanserin, a 5-HT2 receptor antagonist, also showed a tendency to shorten swimming latencies. Latencies of haloperidol-, cis-N-(1-benzyl-2-methyl-pyrrolidin-3-yl)-2-methoxy-5-chloro-4-met hyl- aminobenzamide (YM-09151-2)- and sulpiride-, dopamine D2 receptor antagonists, treated groups did not differ from that seen in the PCP-treated group. Thus, PCP-induced cognitive dysfunction may be improved by sigma receptor ligands.
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PMID:Effect of NE-100, a novel sigma receptor ligand, on phencyclidine-induced cognitive dysfunction. 782 67

The ethanol-like discriminative stimulus effects of N-methyl-D-aspartate (NMDA) antagonists that act at the NMDA recognition site [(D)-4-(3-phosphonoprop-2-enyl)piperazine-2-carboxylic acid (CPPene) and cis-4-phosphonomethyl-2-piperidine carboxylic acid] or within the NMDA associated cation channel [phencyclidine (PCP) and dizocilpine] were evaluated in rats trained to discriminate ethanol or PCP from vehicle in a two-lever discrimination procedure. Three groups of rats were trained to discriminate 1.0, 1.5 or 2.0 g/kg of ethanol from water and one group was trained to discriminate 1.5 mg/kg of PCP from saline. In the ethanol-trained groups, both PCP (1.0-5.6 mg/kg; i.p.) and dizocilpine (0.03-0.3 mg/kg; i.p.) completely substituted for ethanol in every rat tested, although the dizocilpine resulted in only partial substitution in rats trained to discriminate 1.0 g/kg of ethanol. As the training dose of ethanol increased, the potency of PCP and dizocilpine to substitute for ethanol increased. In contrast, CPPene (1-17 mg/kg; i.p.) and cis-4-phosphonomethyl-2-piperidine carboxylic acid (5.6-17 mg/kg; i.p.) resulted in partial substitution for ethanol, with lower amounts of ethanol-appropriate responding as the training dose of ethanol increased. These data indicate that uncompetitive antagonism of NMDA neurotransmission at sites within the cation channel produce discriminative stimulus effects that are similar to those of ethanol, particularly to higher ethanol doses. Neither ethanol (0.5-1.5 g/kg; i.p.) nor CPPene (5.6 and 10 mg/kg) completely substituted for the discriminative effects of PCP. The asymmetrical generalizations between ethanol and PCP are discussed in terms of the mixed discriminative effects of ethanol.
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PMID:Discriminative stimulus effects of ethanol: effect of training dose on the substitution of N-methyl-D-aspartate antagonists. 845 Apr 61

Two series of compounds that are structurally related to benzomorphans, derived by structural modification of arylpiperazines with high 5-HT1A affinity and moderate sigma affinity, were prepared in order to increase sigma affinity and selectivity. All new compounds are N-substituted-omega-(1,2,3,4-tetrahydronaphthalen-1-yl)- or -omega-(1,2-dihydronaphthalen-4-yl)-n-alkylamines with, in some cases, a methoxy group on the tetralin moiety. They were tested in radioligand binding assays on sigma ([3H]DTG and [3H]-(+)-pentazocine), D-2 dopaminergic, 5-HT1A and 5-HT2 serotonergic, and PCP (phencyclidine) receptors. A first set of compounds bearing a 4-(1-substituted)piperazine moiety as terminal fragment on the alkyl chain showed moderate to high sigma affinity (Ki = 5.3-139 nM), the most active and selective being 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n- propyl ]piperazine (14), with probable pronounced sigma 2 affinity (Ki = 5.3 nM on [3H]DTG and Ki = 71 nM on [3H]-(+)-pentazocine). Moreover, compound 13, a 1-benzylpiperazine analogue of 14, preserved a dual high 5-HT1A and sigma affinity (Ki = 3.6 nM on [3H]-5-HT and Ki = 7.0 nM on [3H]DTG). The second set of compounds includes some N-phenylalkyl derivatives of 3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)- n-propylamine that can be considered to be open-chain derivatives of 4-substituted-1-arylpiperazines. Among these compounds that had a lower activity toward sigma binding sites, a high 5-HT1A affinity was found for the N-(3-phenylpropyl) derivative 21 (Ki = 4.4 nM) which demonstrated very good selectivity.
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PMID:New sigma and 5-HT1A receptor ligands: omega-(tetralin-1-yl)-n-alkylamine derivatives. 856 4

The mechanisms of sigma (sigma) receptor ligands-induced neuroprotective effects are controversial because both sigma receptors and phencyclidine (PCP) binding sites of the N-methyl-D-aspartate (NMDA) receptor channel complex have been reported to contribute to these neuroprotective effects. Thus, to clarify the role of sigma receptor in the neuroprotective effects, we examined the effects of 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503), a novel sigma1 receptor agonist with negligible affinity for the NMDA/PCP receptor channel complex, on the hypoxia/hypoglycemia- and exogenously applied NMDA-induced neurotoxicity in the rat primary neuronal cultures. A selective sigma1 receptor agonist, SA4503, significantly suppressed the hypoxia/hypoglycemia-induced neurotoxicity in the cultures, whereas this agonist failed to inhibit the NMDA-induced neurotoxicity. Similarly, (+)-pentazocine ((+)-PTZ), a prototype sigma1 receptor agonist, inhibited the hypoxia/hypoglycemia-induced neurotoxicity, whilst it did not affect the NMDA-induced toxicity in the cultures. These neuroprotective effects of SA4503 and (+)-PTZ were partially blocked by N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine monohydrochloride (NE-100), a putative sigma1 receptor antagonist. These results suggest that the sigma1 receptor subtype plays an important role in the sigma receptor ligands-induced neuroprotective effects via the regulation of excitatory amino acids (EAAs) release from the presynaptic sites.
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PMID:Activation of sigma1 receptor subtype leads to neuroprotection in the rat primary neuronal cultures. 959 56


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