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)

A chromatographic method is developed for quantitative estimation of the collagenase-like enzyme (CLE) activity in extract of adenohypophysis and in preparations obtained during various steps of the enzyme isolation. The enzymatic hydrolysis of Cbz-Gly-Pro-Ala-Gly-Pro-Gly-OCH3 in presence of 2-mercaptoethanol at pH 8.0 was used as a pattern. The products formed were separated by chromatography on the paper; then they were stained with ninhydrin and converted into cupric complexes during extraction with ethanol; the optic density was measured at 510 nm. The optimal conditions for the enzymatic reaction were established. The method enabled to estimate the CLE activity in presence of prolyl carboxypeptidase. The specific effect of the CLE purified preparation on various synthetic peptides is discussed.
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PMID:[Chromatographic method of determining the activity of the collagenase-like enzyme of the adenohypophysis and several findings concerning the specificity of its action]. 88 63

The effects of delta 9-tetrahydrocannabinol (delta 9-THC) in combination with phencyclidine (PCP) or ethanol were examined in rats responding under a fixed-consecutive-number schedule of food presentation. Under this schedule, a minimum of 13 consecutive responses on one lever followed by one response on another lever produced food. When administered alone, PCP (0.1-10.0 mg/kg) and delta 9-THC (0.1-5.6 mg/kg), but not ethanol (0.3-1.7 g/kg), decreased accuracy. PCP, delta 9-THC, and ethanol alone all produced dose-dependent decreases in rate of responding. A dose-effect curve for PCP or ethanol was then redetermined in combination with selected doses of delta 9-THC (0.125-1.75 mg/kg) and the data were analyzed according to the effect-addition and dose-addition models of additivity. When administered in combination, delta 9-THC produced dose-dependent leftward shifts in the PCP dose-effect curves for both accuracy and rate of responding. The interactions for PCP + delta 9-THC combinations were effect-additive for accuracy. In contrast, the type of interaction obtained for PCP + delta 9-THC combinations on rate of responding depended upon the particular doses combined, as well as on the model used to analyze the interactions. According to the effect-addition model, these interactions were additive at low doses of delta 9-THC and supraadditive at the highest dose. However, according to the dose-addition model the interactions at the higher doses of delta 9-THC were infraadditive. Delta 9-THC also shifted the ethanol dose-effect curve for rate of responding to the left but did not alter the ethanol dose-effect curve for accuracy. The interactions for ethanol + delta 9-THC combinations were effect-additive for accuracy and both effect- and dose-additive for rate of responding. The present investigation clearly illustrates the importance of examining an extensive range of dose combinations on different behavioral measures, as well as the use of appropriate analyses in studies designed to evaluate the interactions between drugs.
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PMID:Delta 9-tetrahydrocannabinol interactions with phencyclidine and ethanol: effects on accuracy and rate of responding. 132 18

Rat brain cortex synaptosomes pre-incubated with [3H]norepinephrine were used (1) to provide evidence that part of the NMDA receptors mediating stimulation of norepinephrine (NE) release are located on the noradrenergic varicosities themselves, (2) to characterize these receptors and (3) to examine whether ethanol specifically inhibits the NMDA-evoked NE release via a presynaptic site of action. In synaptosomes superfused with Mg(2+)-free Krebs-Henseleit solution, NMDA (2-min exposure) stimulated tritium overflow in a concentration- and glycine-dependent manner. The stimulatory effect of NMDA was not altered by tetrodotoxin but was abolished by omission of Ca2+ from the superfusion fluid and was considerably reduced in the presence of 1.2 mM Mg2+. DL-(E)-2-Amino-4-methyl-5-phosphono-3-pentanoic acid (CGP 37849; a competitive NMDA receptor antagonist) produced a parallel shift of the concentration-response curve for NMDA to the right, whereas dizocilpine (MK-801; an antagonist at the phencyclidine, PCP, recognition site of the NMDA-gated ion channel) reduced the maximum effect of NMDA. Ethanol inhibited the NMDA-evoked tritium overflow in a concentration-dependent manner. In contrast, in synaptosomes superfused with Ca(2+)-free Krebs-Henseleit solution containing 15 mM K+ throughout, ethanol did not affect the tritium overflow evoked by 2 min introduction of 75 microM Ca2+ into the superfusion fluid. This Ca(2+)-evoked overflow was also not altered by tetrodotoxin and dizocilpine, but was inhibited by the inorganic Ca2+ channel antagonist Cd2+.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Presynaptic site of action underlying the ethanol-induced inhibition of norepinephrine release evoked by stimulation of N-methyl-D-aspartate (NMDA) receptors in rat cerebral cortex. 135 86

Phencyclidine (PCP), a drug inducing schizophrenia-like symptoms in humans, is reported to be a non-competitive antagonist at the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptors. In rats, PCP produces three dose-dependent stages of EEG patterns: 1) increase of cortical desynchronization duration; 2) increase of the amplitude of the high-frequency (20-30 Hz) low-voltage (30-50 microV) cortical background activity; 3) appearance of cortical slow (2-3 Hz) wave-sharp wave complexes. These EEG changes are accompanied by stimulatory-depressive effects such as stereotypy (circling, head weaving) and ataxia. In the present study, the EEG and behavioural effects induced by systemic administration of the NMDA antagonists dizocilpine (MK 801), dextromethorphan (DM), [(+)-alpha-(4-chlorophenyl)-4- [(phenyl)methyl-1-piperidine ethanol] (SL 82.0715), (+)3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), cis-4-phosphonomethyl-2-piperidine-carboxylic acid (CGS 19755) have been compared to those of PCP in rats. The rank of potency for inducing PCP-like EEG stages 1-3 was as follows: MK 801 > PCP > CGS 19755 > CPP. These drugs also induced PCP-like behavioural effects. On the contrary, DM and SL 82.0715, administered up to the dose of 100 mg/kg IP, failed to induce PCP-like behavioural effects and elicited only the stage 1 of PCP-like EEG. These results strongly suggest the involvement of NMDA neurotransmission in the behavioral and EEG effects of PCP.
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PMID:Different capability of N-methyl-D-aspartate antagonists to elicit EEG and behavioural phencyclidine-like effects in rats. 136 27

The effects of injection of various purinoceptor agonists into the hypothalamic paraventricular nucleus in water-loaded and ethanol-anesthetized rats were investigated. Adenosine triphosphate (ATP), beta,gamma-methyleneadenosine 5'-triphosphate (AMP-PCP) and beta,gamma-imidoadenosine 5'-triphosphate (AMP-PNP) potently decreased the outflow of urine in a time- and dose-dependent manner. The ED50 values were approx 70 and 37 nmol for ATP and AMP-PCP, respectively. Adenosine diphosphate (ADP), AMP and adenosine reduced the outflow of urine much less than ATP. Adenosine triphosphate induced concomitant increases in the osmotic pressure of the urine and in the level of arginine-vasopressin (AVP) in plasma. The antidiuretic effect of ATP was blocked by prior injection of quinidine (a P2-purinoceptor antagonist) into the paraventricular nucleus, but not by the prior injection of theophylline (a P1-purinoceptor antagonist). The effect of ATP was also blocked by intravenous injection of an AVP(V1V2)-receptor antagonist, d(CH2)5-D-Tyr(Et)VAVP. The results suggest that ATP injected into the paraventricular nucleus may stimulate a purinoceptor, releasing AVP and inducing the antidiuretic effect through renal AVP(V2) receptors.
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PMID:Antidiuretic effects of purinoceptor agonists injected into the hypothalamic paraventricular nucleus of water-loaded, ethanol-anesthetized rats. 140 98

Ethanol has been shown to antagonize N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission in a number of in vitro systems. Drug discrimination procedures in rats were used to evaluate ethanol as an antagonist of NMDA discrimination and for its ability to produce discriminative stimulus effects similar to those of competitive and noncompetitive NMDA antagonists. Ethanol (300-1500 mg/kg i.p.) failed to antagonize the stimulus effects of 30 mg/kg NMDA, nor did it substitute fully for either the competitive antagonist NPC 12626 nor the noncompetitive antagonist phencyclidine (PCP). A maximum average of 55.4% PCP-lever responding provided evidence for partial substitution in this model. The effects of ethanol on NMDA discrimination are distinct from those previously reported for competitive NMDA antagonists but similar to those of noncompetitive antagonists. On the other hand, ethanol can be distinguished from both competitive and PCP-like noncompetitive NMDA antagonists using drug discrimination procedures.
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PMID:Drug discrimination analysis of ethanol as an N-methyl-D-aspartate receptor antagonist. 146 98

The novel semirigid derivatives (+)-cis-1-[2-phenyl-2-bicyclo[3.1.0]hexyl]piperidine [(+)-8], its enantiomer (-)-8, and (+-)-trans-1-[2-phenyl-2-bicyclo[3.1.0]hexyl]piperidine [(+/-)-9] were synthesized as probes to investigate the mode of interaction of phencyclidine (PCP) with its binding site on the N-methyl-D-aspartate receptor complex. Each target compound was obtained in five steps starting from cyclopent-2-enone. (+)- and (-)-8 were obtained in greater than 98% optical purity through three recrystallizations from ethanol of the (S)-(+)- and (R)-(-)-mandelate salts of intermediate (+-)-cis-2-phenyl-2-bicyclo[3.1.0]hexylamine ([(+/-)-16]. Crystallization of the (R)-(-)-mandelate salt afforded (1R,2R,5S)-(-)-16, whereas the (S)-(+)-mandelate salt afforded (1S,2S,5R)-(+)-16; the absolute configuration was determined by single-crystal X-ray analysis of (-)-16.(R)-(-)-mandelate. Single-crystal X-ray analysis of (+/-)-9-picrate confirmed its trans configuration and provided conformational data. (+)- and (-)-8 and (+/-)-9 were examined for their ability to interact with PCP and sigma binding sites in vitro using [3H]TCP and [3H]pentazocine as radioligands. The binding was compared with that of PCP and contrasted with the rigid symmetrical phencyclidine derivatives cis- and trans-1-[3-phenyl-3-bicyclo[3.1.0]hexyl]piperidines (6 and 7). The results of the study indicated that the conformations of PCP represented by 6-9 are not optimal for potent interaction at either of these sites. Affinities ranged from 582 nM [(+/-)-9] to 29,000 nM [(+)-8] at PCP binding sites and from 1130 nM [(-)-8] to 16,300 nM (7) at sigma sites. In this assay, PCP exhibited affinities of 64.5 nM at PCP and 1090 nM at sigma sites. Qualitative correlation between the sigma and PCP binding data suggests some similarities between these binding sites. An axial phenyl and equatorial piperidine ring with the nitrogen lone pair of electrons antiperiplanar to the phenyl ring has been postulated as the receptor-active conformation of PCP-like ligands at the PCP binding site. Comparison of the binding data of 7-9 with that of the previously described methylcyclohexyl-PCP derivatives allowed its rationalization in terms of this model. It is likely that the lowered affinity in this bicyclo[3.1.0]hexane series is a consequence of nonoptimal geometry (pseudoequatorial phenyl or pseudoboat) for binding as opposed to the presence of steric bulk which proved deleterious in the methylcyclohexyl-PCP derivatives.
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PMID:Synthesis, configuration, and activity of isomeric 2-phenyl-2-(N-piperidinyl)bicyclo[3.1.0]hexanes at phencyclidine and sigma binding sites. 146 99

The effects of buprenorphine on behavior reinforced by smoked cocaine base and orally delivered phencyclidine (PCP), ethanol and saccharin were compared. There were six groups of four to five rhesus monkeys. Group 1 contained four monkeys that had been trained to smoke cocaine base under progressive ratio (PR) or fixed ratio (FR) schedules. Up to eight smoke deliveries (2 mg/kg) were available during daily 3-hr sessions. Each delivery was separated by a 15-min timeout. The remaining groups received concurrent access to different combinations of orally delivered liquids as follows: group 2, PCP (0.25 mg/ml) and water; group 3, saccharin (0.03% w/v) and water; group 4, PCP and saccharin; group 5, ethanol (8% w/v) and water; and group 6, ethanol and PCP. Saline or buprenorphine (0.003, 0.012, 0.05, 0.2 and 0.8 mg/kg) injections were given i.m. 30 min before each session for 5 consecutive days. Buprenorphine produced a dose-dependent reduction in behavior maintained by PCP, ethanol or saccharin in all of the six groups. In group 1, the suppressant effects of buprenorphine on cocaine base smoking were greater in the two monkeys that responded under FR 5 schedules than in the two that responded under PR schedules. When PCP and saccharin were concurrently available (group 4), buprenorphine had a greater suppressant effect on PCP than when water was concurrently present (group 2). Buprenorphine produced nearly a complete suppression in saccharin-maintained responding at doses of 0.012 mg/kg and higher in groups 3 and 4. Buprenorphine reduced ethanol deliveries to about 50% at doses of 0.012 mg/kg and higher in group 5. When PCP and ethanol were concurrently available (group 6), buprenorphine had an effect on PCP and ethanol that was similar to that found when the drugs were available concurrently with water. These results suggest that buprenorphine suppresses behavior maintained by several drug and nondrug substances, and it further suppresses PCP-maintained behavior that is already reduced by a nondrug alternative reinforcer.
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PMID:Buprenorphine's effects on self-administration of smoked cocaine base and orally delivered phencyclidine, ethanol and saccharin in rhesus monkeys. 156 Mar 73

A three-way crossover study was performed to determine the influence of delta 9-tetrahydrocannabinol (THC) and ethanol (EtOH) separately upon phencyclidine (PCP) disposition in dogs. Seven dogs were given three single dose treatments: 1.5 mg PCP kg-1 i.v., 1.5 mg PCP kg-1 i.v. with 0.4 mg kg-1 THC i.v., and 1.5 mg PCP kg-1 i.v. with 1.25 g EtOH kg-1 i.v. PCP was measured in plasma samples collected for 24 h after administration of each treatment, with several pharmacokinetic parameters calculated from the plasma concentration vs time data. The PCP serum Cls values were significant change in V beta or t1/2. EtOH did not induce significant changes in any PCP pharmacokinetic parameter, although mean Cls and V beta were increased. These results confirm the observed THC inhibition of PCP metabolism, and suggest that the enhanced pharmacologic action of PCP by THC may result from higher serum PCP concentrations. These results further suggest that enhanced PCP actions by acute EtOH administration may result from increased PCP distribution to the CNS.
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PMID:Effects of ethanol and delta 9-tetrahydrocannabinol on phencyclidine disposition in dogs. 164 25

The Flinders Sensitive Line (FSL) of rats has been selectively bred to have increased sensitivity to cholinergic agonists. However, these rats exhibit altered responsiveness to a number of noncholinergic agents, such as apomorphine, buspirone and ethanol. This study compared the FSL and control Flinders Resistant Line (FRL) rats in terms of their hyperthermic response to the phencyclidine (PCP) receptor agonist, MK-801 (0.2 mg/kg SC) and their MK-801 binding characteristics. We have found that FSL rats react with a delayed hyperthermia, having a significantly lower hyperthermia for the first 120 min of observation. Thereafter the response does not differ in FSL and FRL rats. Both groups had similar affinities and numbers of [3H]MK-801 binding sites in the hippocampus/cerebral cortex. Pretreatment with scopolamine (1 mg/kg SC) failed to affect MK-801-induced hyperthermia in either line of rats. These findings suggest that selective breeding of FSL rats attenuated the secondary mechanisms involved in the PCP receptor-mediated hyperthermic response. However, by itself cholinergic supersensitivity does not appear to be a major factor in the blunted responsiveness of FSL rats to MK-801.
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PMID:Decreased hyperthermic effect of MK-801 in selectively bred hypercholinergic rats. 186 61


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