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)

Recently, the presence of two high affinity binding sites for phencyclidine were described in guinea pig brain, with one site coupled to the glutamate excitatory amino acid receptor, specifically activated by N-methyl-D-aspartate (NMDA) (site 1) and the other site associated with the dopamine (DA) reuptake carrier (site 2). Phencyclidine and its analogs, as well as the benzomorphan opiates, are known to interact with binding sites for phencyclidine. In this study, the equilibrium dissociation constants (Kd) of these compounds for the two binding sites for phencyclidine were determined. Phencyclidine and 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP), an analog of PCP, were essentially non-selective between the two sites and also were the two drugs of the group observed to have the highest affinity for site 2. (+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5,10-imine [(+)MK801] was the most selective agent for site 1, while none of the drugs tested showed selectivity for site 2. In humans, phencyclidine produces psychotomimetic effects, while (+)MK801 has been reported to produce minimal, if any, psychotomimetic effects, at doses sufficient to reduce seizures. These clinical observations, in conjunction with the present biochemical binding data, suggest that (+)MK801 may serve as a "marker" for site 1 and that the psychotomimetic effects of phencyclidine might be mediated by site 2.
Neuropharmacology 1990 Sep
PMID:Specificity of phencyclidine-like drugs and benzomorphan opiates for two high affinity phencyclidine binding sites in guinea pig brain. 196 80

With an eye toward the development of novel atypical antipsychotic agents, we have studied the structure-affinity relationships of N,N'-di-o-tolylguanidine (DTG, 3) and its congeners at the haloperidol-sensitive sigma receptor. A number of DTG analogues were synthesized and evaluated in in vitro radioligand displacement experiments with guinea pig brain membrane homogenates, using the highly sigma-specific radioligands [3H]-3 and [3H]-(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine and the phencyclidine (PCP) receptor specific compounds [3H]-N-[1-(2-thienyl)-cyclohexyl]piperidine and [3H]-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10- imine. The affinity of N,N'-diarylguanidines for the sigma receptor decreases with increasing steric bulk of ortho substituents larger than C2H5. Hydrophobic substituents are generally preferred over similarly positioned hydrophilic ones. Furthermore, electroneutral substituents are preferred over strongly electron donating or withdrawing groups. Significant binding to the sigma receptor is usually retained as long as at least one side of the guanidine bears a preferred group (e.g. 2-CH3C6H5). Replacement of one or both aryl rings with certain saturated carbocycles (e.g. cyclohexyl, norbornyl, or adamantyl) leads to a significant increase in affinity. By combining the best aromatic and best saturated carbocyclic substituents in the same molecule, we arrived at some of the most potent sigma ligands described to date (e.g. N-exo-2-norbornyl-N'-(2-iodophenyl)guanidine, IC50 = 3 nM vs [3H]-3). All of the compounds tested were several orders of magnitude more potent at the sigma receptor than at the PCP receptor, with a few notable exceptions. This series of disubstituted guanidines may be of value in the development of potential antipsychotics and in the further pharmacological and biochemical characterization of the sigma receptor.
J Med Chem 1990 Sep
PMID:Synthesis and structure-activity relationships of N,N'-di-o-tolylguanidine analogues, high-affinity ligands for the haloperidol-sensitive sigma receptor. 197 75

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.
Can J Physiol Pharmacol 1990 Sep
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

Using a two-lever operant drug discrimination paradigm, rats have been trained to discriminate between the administration of saline and R-(+)-HA-966 (R-(+)-3-amino-1-hydroxypyrrolid-2-one, 30 mg/kg i.p.) an antagonist at the glycine modulatory site on the N-methyl-D-aspartate (NMDA) receptor/ion channel complex. Drug-appropriate responding was not induced in stimulus generalisation experiments when the non-competitive NMDA receptor antagonist, phencyclidine (PCP, 1-8 mg/kg i.p.) was substituted for (+)-HA-966. Similarly, (+)-HA-966 (6-50 mg/kg i.p.) did not induce drug-appropriate responding in animals trained to discriminate PCP (3 mg/kg i.p.) from saline. The results suggest that the behavioural profile of compounds attenuating the actions of NMDA via blockade of the glycine modulatory site may be substantially different from those acting at the ion channel of the NMDA receptor complex.
Eur J Pharmacol 1990 Sep 04
PMID:The discriminative stimulus properties of (+)-HA-966, an antagonist at the glycine/N-methyl-D-aspartate receptor. 214 38

Two highly selective radiolabeled probes for sigma receptors were found to bind with high affinity and capacity to membranes from undifferentiated PC12 cells. [3H]1,3-di-o-tolylguanidine [( 3H]DTG) bound with Kd = 23.7 +/- 4.6 nM and Bmax = 2025 +/- 660 fmol/mg protein. The Kd and Bmax for [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ([3H](+)-3-PPP) were 86.3 +/- 21.6 nM and 1539 +/- 242 fmol/mg protein, respectively. These binding parameters were comparable to those observed in guinea pig brain, although the Kd for [3H](+)-3-PPP was 3-fold higher in the PC12 membranes. Both the PC12 and guinea pig brain sites exhibited high affinity for haloperidol, moderate affinity for phencyclidine (PCP), and negligible affinity for MK-801, apomorphine, and (-)-sulpiride. These data suggest a relationship of the PC12 site to sigma receptors. However, all (+)-opiates [+)-benzomorphans and (+)-morphinans) tested bound with markedly lower affinity to the PC12 site compared to guinea pig brain. These include (+)-N-allylnormetazocine [+)-SKF 10,047), (+)-pentazocine, and dextrallorphan. In fact, PC12 sites exhibited preference for (-)-benzomorphans, the reverse stereoselectivity of guinea pig brain sites. Binding of [3H]N-[1-(2-thienyl)cyclohexyl]piperidine [( 3H]TCP) could not be detected, demonstrating absence of PCP receptors on this cell line. Differentiation of cells by treatment with nerve growth factor had no effect on sigma binding parameters. Membranes from guinea pig brain and PC12 cells were photoaffinity-labeled using [3H]azido-di-o-tolylguanidine. In guinea pig brain, a polypeptide of 25 kDa was specifically labeled. However, label was incorporated into polypeptides of 18 kDa and 21 kDa in membranes from PC12 cells. In view of the otherwise similar binding characteristics, the marked differences in affinity for (+)-benzomorphans and molecular weight suggest that PC12 cells contain a molecular form of sigma receptor distinct from that predominant in guinea pig brain. This raises the possibility of multiple sigma receptor types.
Brain Res 1990 Sep 17
PMID:A sigma-like binding site in rat pheochromocytoma (PC12) cells: decreased affinity for (+)-benzomorphans and lower molecular weight suggest a different sigma receptor form from that of guinea pig brain. 217 17

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.
Br J Pharmacol 1990 Sep
PMID:CI-977, a novel and selective agonist for the kappa-opioid receptor. 217 14

The effect of phencyclidine (PCP) on carbachol-induced phosphoinositol hydrolysis was examined in rat brain slices taken from cortex, caudate-putamen and hippocampus. In all three regions studied, PCP significantly inhibited carbachol-induced [3H]inositol phosphate accumulation working as low as 10(-6) M in the cerebral cortex. Because PCP has been shown to act at two sites, a PCP-site and a sigma site, various PCP-like agonists [levoxadrol (Lev), dexoxadrol (Dex) and MK-801 [(+)-5-methyl-10,11-dihydro- 5H-dibenzo(a,b)cyclo-hepaten-5, 10-imine maleate]] as well as sigma agonists [(+)-SKF10047 and 1,3-di(2-toly)guanidine (DTG) were examined for their effects on carbachol-induced phosphoinositol hydrolysis. All but MK-801 significantly inhibited the carbachol action; however, their order of potencies, Lev greater than or equal to Dex much greater than PCP greater than or equal to DTG greater than or equal to (+)-SKF10047 differed from those of other known PCP interactions at PCP and sigma sites. Inasmuch as it is known that PCP competes for binding at muscarinic sites, we examined the effects of PCP, Lev, Dex, DTG and MK-801 on the binding of L-[3H]-3-quinuclidinyl benzilate to its muscarinic site. All blocked L-[3H]-3-quinuclidinyl benzilate binding and exhibited a rank order of potency almost identical to that obtained in the inositol studies with Lev greater than Dex much much greater than DTG much greater than PCP MK-801. In addition, the IC50 values obtained from both studies were very similar. It is concluded that PCP, PCP-like compounds and sigma agonists block carbachol-induced inositol-phosphate accumulation by blockade of muscarinic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
J Pharmacol Exp Ther 1990 Sep
PMID:Inhibition of carbachol-induced inositol phosphate accumulation by phencyclidine, phencyclidine-like ligands and sigma agonists involves blockade of the muscarinic cholinergic receptor: a novel dioxadrol-preferring interaction. 220

The activities of several proline-specific endo- and exopeptidases were determined in homogenates of immunocytochemically defined cultures of astrocytes, oligodendrocytes and neurones obtained from rat cerebral cortex. Astrocytes are significantly enriched in post-proline cleaving dipeptidyl peptidase II, prolidase and aminopeptidase P activities; neurones and astrocytes contain prolyl endopeptidase. Dipeptidyl peptidase IV and prolyl carboxypeptidase activities are low or absent in the cultures. The physiological significance of these findings is discussed.
Brain Res 1990 Sep 10
PMID:Proline-specific proteases in cultivated neuronal and glial cells. 228 78

Histrionicotoxin, a spiropiperidine alkaloid, and twenty-two analogs inhibited binding of [3H]perhydrohistrionicotoxin [( 3H]H12-HTX) and of [3H]phencyclidine [( 3H]PCP) to sites on the acetylcholine receptor-ion complex of Torpedo electroplax membranes. Structural alterations to the nitrogen (secondary amine) or oxygen (alcohol) functions or to the five carbon and four carbon side chain of histrionicotoxin altered the potency versus [3H]H12-HTX and [3H]PCP binding measured in the presence or absence of a receptor agonist, carbamylcholine. Histrionicotoxin itself was 3-fold more potent versus [3H]PCP binding than versus [3H]H12-HTX binding. N-Methylation or O-acetylation increased this difference, while alterations to the side chains either slightly decreased or markedly increased this difference. Histrionicotoxin was some 3.5-fold more potent versus [3H]H12-HTX binding in the presence of carbamylcholine than in its absence. O-Acetylation increased this selectivity for the carbamylcholine-activated state of the receptor channel complex, while alterations in the side chains either reduced or increased the selectivity. Histrionicotoxin was some 2.2-fold more potent versus [3H]PCP binding in the presence of carbamylcholine than in its absence. N-Methylation of O-acetyl-histrionicotoxin greatly increased this selectivity, while alterations in the side chains either reduced or had no effect on selectivity.
Biochem Pharmacol 1985 Sep 01
PMID:Binding of [3H]perhydrohistrionicotoxin and [3H]phencyclidine to the nicotinic receptor-ion channel complex of Torpedo electroplax. Inhibition by histrionicotoxins and derivatives. 241 60

Patch-clamp techniques were used to record acetylcholine- (ACh) activated single-channel currents in cell-attached membrane patches from myotubes of the mouse cell line, C2. The effects of the phenothiazine derivative chlorpromazine (CPZ) and of the hallucinogen phencyclidine (PCP) on ACh-activated single-channel properties were studied under conditions where both compounds are positively charged (pH 7.2). The single-channel conductance was unaffected by either CPZ or PCP at concentrations ranging from 10 to 500 nM. 10-200 nM-CPZ and PCP led to shortened mean burst times. CPZ and PCP effects on mean burst times were voltage independent and did not vary in a simple linear manner with concentration. 10-200 nM-CPZ and PCP did not reduce channel opening frequencies, suggesting that the fraction of non-conducting state (occupied, blocked or desensitized) favoured at equilibrium was not significant at these concentrations. On the other hand, concentrations of CPZ and PCP higher than 300 nM did lead to depressed channel opening frequencies. In addition, we observed that, at these concentrations, the shortened burst duration reverses to the longer values found at lower effector concentrations. The effects of CPZ and PCP on ACh-activated single-channel kinetics are interpreted in terms of current models of ACh-receptor structure and conformational transitions.
J Physiol 1986 Sep
PMID:Effects of chlorpromazine and phencyclidine on mouse C2 acetylcholine receptor kinetics. 243 54


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