Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.16.2 (PCP)
 3,761 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

(+)-N-Allylnormetazocine (NANM) binds to at least two sites in the mammalian central nervous system, a high-affinity, haloperidol-sensitive site and a lower-affinity site identified as the phencyclidine (PCP) receptor. The relevance of these sites to the discriminative stimulus properties of (+)-NANM was evaluated in rats trained to discriminate (+)-NANM from saline. Drugs with a high affinity for the haloperidol-sensitive site, including haloperidol, (+)-ketocyclazocine, 1,3-di-ortho-tolyl-guanidine and (-)-butaclamol failed to substitute for the (+)-NANM stimulus. In addition, when they were tested in combination with (+)-NANM, only haloperidol evidenced any antagonistic effects. The antagonistic effects of haloperidol were incomplete and only occurred at doses that substantially disrupted responding. Evidence obtained earlier that (+)-3-(3-hydroxyphenyl)-N-(1-propyl) piperidine could antagonize (+)-NANM was not replicated. On the other hand, PCP-like drugs from diverse chemical classes, including PCP, ketamine, MK-801, (-)-2-methyl-3,3-diphenyl-3-propanolamine, etoxadrol and dextrorphan, all substituted fully for the (+)-NANM stimulus with a potency predicted by their relative potency for PCP-like discriminative stimulus effects and relative affinity for the PCP receptor. Taken together, these results fail to provide evidence for an important role for the high-affinity haloperidol-sensitive binding site for (+)-NANM in its discriminative stimulus properties. Instead, activity at the PCP receptor is predictive of (+)-NANM-like effects.
 ...
PMID:Substitution and antagonism in rats trained to discriminate (+)-N-allylnormetazocine from saline. 247 25

This study tested structural analogs of phencyclidine (PCP) using drug discrimination procedures to determine which analogs produced discriminable effects similar to those of PCP. It also tested the utility of multiple-drug discrimination training (PCP versus other drugs or saline) as a method for increasing the specificity produced by training. All discrimination training took place in two-lever operant compartments using FR-10 reinforcement of presses on the correct lever. During training, rats were required to concurrently discriminate PCP from one or more other drug conditions. Rats in group 1 discriminated PCP (lever 1) versus saline (lever 2). Rats in group 2 discriminated PCP (lever 1) versus saline, fentanyl, phenobarbital, amphetamine, or mescaline (lever 2). In both groups 1 and 2, the required discriminations were rapidly learned. The percentage of PCP choices and the ED50 doses obtained during tests for generalization did not differ significantly in groups 1 and 2. Drugs to which responding on the PCP lever generalized included 1-[1-(2-thienyl)cyclohexyl]piperidine, N-ethyl-1-phenylcyclohexylamine, 1-phenylcyclohexylamine, ketamine, 1-(1-phenylcyclohexyl)morpholine, 1-[1-(2-thienyl)cyclohexyl]morpholine, N,N-diethyl-1-phenylcyclohexylamine, N-(iso-propyl)-1-phenylcyclohexylamine, N-methyl-1-phenylcyclohexylamine, N-(n-propyl)-1-phenylcyclohexylamine, Dextrorphan, (dl)-N-allyl-N-normetazocine, N-N-dimethyl-1-phenylcyclohexylamine, N-(n-butyl)-1-phenylcyclohexylamine, 1-[1-(2-thienyl)cyclohexyl]pyrrolidine, and N-(s-butyl)-1-phenylcyclohexylamine, in agreement with previous reports. Rats in group 3 discriminated PCP (lever 1) versus saline, cyclazocine, dextrorphan, phenobarbital, or mescaline (lever 2).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Discriminable effects of phencyclidine analogs evaluated by multiple drug (PCP versus OTHER) discrimination training. 249 47

We have used a variety of selective radioligands to identify and localize sigma- and phencyclidine (PCP)-binding sites in rat endocrine organs. [3H]Haloperidol-labeled sigma-receptors were identified in membrane homogenates of rat pituitary, adrenal, testis, and ovary which had kinetic and pharmacological characteristics similar to those of the well characterized sigma-receptors in rat cerebellum. The highest density of sigma-receptors was present in the ovary, with progressively lower densities present in the testis, pituitary, adrenal, and cerebellum, respectively. In autoradiographic studies, sigma-receptors [labeled with d-3-(3-hydroxyphenyl)N-(1-propyl-2,3-[3H]piperidine or [3H]1,3-di-(2-tolyl)guanidine] were discretely localized within the endocrine tissues. In the pituitary, the highest density of sigma-receptors was found in the anterior lobe. In the adrenal, sigma-receptors were localized primarily in the cortex. In the testis, sigma-receptors were present in highest concentrations in the ductuli efferentes and ductus epididymis; lower densities of binding sites were present in the seminiferous tubules, and no binding was seen in the interstitial tissue. In the ovary, sigma-receptors were localized in high density in the maturing follicles, and lower densities were present in resting follicles. After hypophysectomy, there were relative increases in the densities of sigma receptors in the remaining tissue in the adrenal gland and testis. In contrast, hypophysectomy resulted in a marked depletion of sigma-binding sites in the ovary. The data from hypophysectomized rats indicate that the highest densities of sigma-receptors in the ovary are localized to (LH-dependent) maturing follicles, while sigma-binding sites in adrenal and testis are localized to cells that are not dependent on trophic maintenance by the pituitary. In contrast, high affinity PCP receptors were not detected in pituitary, adrenal, testis, or ovary either by homogenate binding studies with 3,4-[3H]N-[1-(2-thienyl)cyclohexyl]piperidine or in vitro autoradiography using 3,4-[3H]N-[1-(2-thienyl)cyclohexyl]piperidine and d-[3H]5-methyl-10,11-dihydro-5H-dibenzo-[a,d] + cyclohepten-5,10-imine. In summary, the data suggest that the reported endocrine effects of PCP and the prototypic sigma-receptor agonist N-allylnormetazocine are probably mediated either through direct action on sigma-receptors in the pituitary and/or target endocrine organs or by actions on sigma- and/or PCP receptors in brain.
 ...
PMID:Sigma-receptors in endocrine organs: identification, characterization, and autoradiographic localization in rat pituitary, adrenal, testis, and ovary. 253 73

We studied the effects of several prototypic sigma site ligands on the binding of [3H]dextromethorphan ([3H]DM) to guinea pig brain. Haloperidol, 3-(-3-Hydroxyphenyl)-N-(1-propyl)piperidine [+)-3-PPP) and (+)-N-allyl-N-normetazocine [+)-NANM or (+)-SKF10,047), which are potent sigma site ligands, showed high affinity for [3H]DM binding sites. The rank order of potency of sigma ligands, as indicated by the Ki values for the high-affinity sites is: haloperidol greater than (+)-pentazocine greater than (+)-cyclazocine greater than (+)-SKF10,047 greater than (-)-butaclamol much greater than (+)-butaclamol greater than (-)-SKF10,047. This rank order of potency is similar to that for the sites labeled with [3H](+)-3-PPP and [3H](+)-SKF10,047. The (+)-isomers of several benzomorphans displayed higher affinity than the (-)-isomers. (-)-Butaclamol competed against [3H]DM binding more effectively than the (+)-isomer, displaying the same stereospecificity shown for sigma sites. The findings reported here demonstrate that there are previously unrecognized similarities between DM and sigma sites. It is evident that further exploration of the DM, sigma and phencyclidine (PCP) sites will be necessary to establish the physiological role and therapeutic potential of these sites.
 ...
PMID:The effect of prototypic sigma ligands on the binding of [3H]dextromethorphan to guinea pig brain. 253 77

An organizing role for the N-methyl-D-aspartate (NMDA) receptor/channel has been suggested in the development of the retinotectal projection in Rana pipiens. The regional distributions of NMDA, phencyclidine (PCP) and quisqualic acid (QA) receptors were quantified using in vitro autoradiography in the tectum of normal and surgically produced 3-eyed juvenile frogs. NMDA and QA receptor binding was highest in the pretectum. Of the tectal layers, the superficial retinotectal synaptic zone, layer 9, had the highest amount of NMDA and QA receptor binding. Moderate binding was observed in layer 5, with little binding in the cellular layer 6. No specific [3H]N-(1-[2-thienyl]cyclohexyl) piperidine ([3H]TCP) binding was observed in any of the tectal regions.
 ...
PMID:Quantitative autoradiographic localization of NMDA, quisqualate and PCP receptors in the frog tectum. 253 81

The distribution of [3H]glycine binding sites was compared with that of N-methyl-D-aspartate (NMDA) receptors labelled with L-[3H]glutamate, and with that of phencyclidine (PCP) receptors labelled with [3H]1-(1-(2-thienyl)-cyclohexyl)piperidine ([3H]TCP) in sections from 7 normal human hippocampi. The results indicate that strychnine-insensitive glycine binding sites are present in high concentrations in CA1 and the molecular layer of the dentate gyrus. This distribution is very similar to the distributions of NMDA and PCP receptors in the human hippocampus.
 ...
PMID:[3H]glycine binding sites, NMDA and PCP receptors have similar distributions in the human hippocampus: an autoradiographic study. 253 83

Pretreatment of guinea pig brain membranes with 1-[1-(3-isothiocyanatophenyl)cyclohexyl]piperidine (Metaphit) caused irreversible and differential inhibition of ligand binding to sigma (sigma) receptors. The concentration of Metaphit required to produce 50% inhibition of binding of [3H]1,3-di-o-tolylguanidine ([3H]DTG), [3H](+)-3-(3-hydroxy-phenyl)-N-(1-propyl)piperidine ([3H](+)-3-PPP), and [3H](+)-N-allylnormetazocine ([3H](+)-SKF 10,047) to sigma receptors was 2, 10 and 50 microM, respectively. This compares to a value of 10 microM for inhibition of [3H]1-[1-(2-thienyl)cyclohexyl]piperidine [( 3H]TCP) binding to phencyclidine (PCP) receptors. While Metaphit was an irreversible, non-competitive inhibitor at PCP receptors, this compound produced irreversible, competitive inhibition at sigma receptors.
 ...
PMID:Acylation of sigma receptors by Metaphit, an isothiocyanate derivative of phencyclidine. 254 47

A phencyclidine (PCP) receptor binding site has been solubilized in an active ligand-binding state from rat cerebral cortical membranes with sodium deoxycholate. Optimal receptor solubilization occurs at a detergent/protein ratio of 0.5 (w/w); for 5 mg protein/ml solubilized with 0.25% sodium deoxycholate, about 60% of the protein and 25% of the receptor is solubilized. Specific binding of either [3H]-N-[1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP) or [3H]MK-801 is measurable by filtration through Sephadex G-50 columns or glass fiber filters; more than 60% of the binding activity is stable after 48 h at 4 degrees C. In the presence of detergent, [3H]TCP binding exhibits a Kd of 250 nM, a Bmax of 0.56 pmol/mg protein, and a pharmacological profile consistent with that of the membrane-bound PCP receptor, although most drugs bind with affinities 2 to 8 fold lower than in membranes. Upon reduction of detergent concentration, binding parameters approximate those for the membrane-bound receptor ([3H]TCP binding: Kd = 48 nM, Bmax = 1.13 pmol/mg protein).
 ...
PMID:Solubilization of phencyclidine receptors from rat cerebral cortex in an active ligand binding state. 254 80

Results of correlation analyses comparing rank-order affinities with rank-order potencies of (+)SKF-10,047, phencyclidine (PCP), and several PCP analogs support the involvement of [3H]-1-[1-(2-thienyl)cyclohexyl]piperidine binding sites (TCP sites) in mediating both the discriminative stimulus properties of PCP and production of 180 degrees perseveration in a 4-arm radial maze. For the same group of drugs, no significant relationship was found to exist between affinities at haloperidol-sensitive (+)[3H]SKF-10,047 binding sites (H-S-SKF sites) and potencies. Also, H-S-SKF sites were found to lack pharmacological selectivity and to be localized in the microsomal fraction of cells. It is concluded that TCP sites may represent receptors which mediate effects not only of PCP, but also of (+)SKF-10,047. In addition, the possibility that H-S-SKF sites may represent a type of membrane-bound enzyme is discussed.
 ...
PMID:Phencyclidine/SKF-10,047 binding sites: evaluation of function. 254 93

Thirty-seven arylcyclohexylamines including phencyclidine (PCP) and derivatives, N[1-(2-thienyl)cyclohexyl]piperidine (TCP) and derivatives and N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine (BTCP) were assessed for their ability to inhibit [3H]PCP binding and [3H]dopamine ([3H]DA) synaptosomal uptake. Their pharmacological property (ataxia) was measured by means of the rotarod test. A very good correlation was observed between the inhibition of [3H]PCP binding and the [3H]DA uptake only for arylcyclohexylamines bearing an unmodified phenyl group. Conversely the comparison between the inhibition of [3H]PCP binding and the activity in the rotarod test shows a good correlation with arylcyclohexylamines having any aromatic group (phenyl, substituted phenyl and thienyl rings). This study outlined a new compound (BTCP) without ataxic effect, which is one of the more potent inhibitors of the [3H]DA uptake (IC50 = 8 nM) and which seems very specific since it has a low affinity for [3H]PCP receptors (IC50 = 6 microM). These data show that the aromatic group of the compounds leads to molecules that bind differently to the PCP receptor and to the DA uptake complex. They also suggest that the behavioral properties of arylcyclohexylamines revealed by the rotarod test occur essentially as a result of an interaction with the sites labeled with [3H]PCP and that TCP is more selective than PCP itself in this recognition.
 ...
PMID:Role of the aromatic group in the inhibition of phencyclidine binding and dopamine uptake by PCP analogs. 254 5


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>