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 new sensitive and specific GC-MS assay was developed to quantify monohydroxy metabolites of phencyclidine (PCP) from biological samples. The method is based on the two-step extraction of PCP and related basic metabolites in an organic solvent followed by a capillary column GC separation and mass selective detection of the extract derivatized with N,O-bis(trimethylsilyl)trifluoroacetamide. The detection limit of the method is about 5 pmol with a linear standard curve to 3 nmol/injection. The assay was used for the quantification of monohydroxy metabolites in the urine of PCP-dosed mice and rats. A new compound (specifically selected for this study), 1-phenyl-1-(1-[3-hydroxymethyl]piperidinyl)cyclohexane, was used as the internal standard. The internal standard was selected to closely mimic the chemical characteristics of potential alicyclic hydroxy metabolites of PCP. The in vitro biotransformation of PCP by mouse and rat liver microsomes also was studied. The presence of a recently identified metabolite, 3-phenyl-3-(1-piperidinyl)-trans-cyclohexanol was confirmed. A new metabolite, 1-phenyl-1-(1-piperidinyl-3-ol)cyclohexane, was identified and quantified in the urine and liver microsomal preparations.
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PMID:Hydroxy metabolites of phencyclidine. Identification and quantitation of two novel metabolites. 290 Jul 29

An autoradiographic analysis of high-affinity binding sites for the vesicular acetylcholine transport blocker [3H]vesamicol (2-(4-phenylpiperidino) cyclohexanol; AH 5183) was conducted in rat brain. [3H]Vesamicol binding was displaced 52-99% by DPPN [( 2,3,4,8]-decahydro-3-(4-phenyl-1-piperidinyl)-2-napthalenol) (IC50 = 14 nM) and by ketanserin (500 nM), haloperidol (43 nM), and vesamicol analogs, but not by drugs selective for adenosine, adrenergic, amino acid, calcium channel, monoaminergic, opioid, PCP, sigma, or several other receptor classes. [3H]Vesamicol binding was most concentrated in the interpeduncular nucleus and fifth and seventh cranial nerve nuclei. Moderate binding was found in the lateral caudate-putamen, medial nucleus accumbens, olfactory tubercle, vertical and horizontal diagonal bands of Broca, and basolateral amygdala. The distribution of [3H]vesamicol binding was similar to distributions of acetylcholine (r = 0.88), acetylcholine esterase (r = 0.97), choline acetyltransferase (ChAT) (r = 0.97), and [3H]hemicholinium-3 binding sites (r = 0.95-0.99). Lower correlations were obtained between [3H]vesamicol and muscarinic receptor densities (r = 0.50-0.70). Few exceptions to the match between binding and cholinergic neuronal markers were found, e.g., the molecular layer of the cerebellum and the thalamus. Lesions of cholinergic neuronal projections to the neocortex or hippocampus reduced [3H]vesamicol binding in each of these regions, but to a lesser extent than reductions in ChAT. [3H]Vesamicol binding sites appear to be anatomically associated with brain cholinergic neurons, a locus that is consistent with the control by this site of vesicular acetylcholine uptake.
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PMID:[3H]vesamicol binding in brain: autoradiographic distribution, pharmacology, and effects of cholinergic lesions. 297 45

The interactions of the hallucinogenic drug PCP [1-(1-phenylcyclohexyl)piperidine] and some of its analogs with the nicotinic acetylcholine receptor-ionic channel complex were studied using electrophysiological techniques. The peak amplitude and the decay time constant of the nerve-evoked end-plate current (EPCs) recorded from the frog sartorius muscle were reduced by all the analogs in a concentration-dependent manner (IC50 between 5 and 90 microM). PCP, TCP [1-[1-(2-thienyl)cyclohexyl]-piperidine] and PCE (N-ethyl-1-phenylcyclohexylamine), among other analogs, caused a negative slope conductance in the current-voltage relationship at hyperpolarized potentials and a voltage- and time-dependent depression of the peak amplitude of the EPC. When the piperidine ring of the PCP molecule was substituted by a morpholino ring, as in 1-(1-phenylcyclohexyl)morpholine and 1-[1-(2-thienyl)-cyclohexyl]morpholine, the potency decreased and the negative conductance was eliminated. The removal of the piperidine ring of PCP in 1-phenylcyclohexylamine and the hydroxylation of the cyclohexane ring in 4-phenyl-4-piperidino-cyclohexanol reduced the potency and produced double exponential decays at potentials between +50 and -50 mV. At -100 mV, the potency for decreasing peak EPC amplitude was well correlated with the potency for reducing the decay time constant for all the analogs. The voltage- and time-dependent depression of the EPC amplitude was reduced by substitution of a morpholino ring and by the elimination of the piperidine ring of PCP. The behaviorally active analogs were the most potent EPC blockers, which suggests a synaptic role for the production of depressant behavioral effects observed with PCP.
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PMID:Effects of phencyclidine and its analogs on the end-plate current of the neuromuscular junction. 348 35

The following monohydroxy derivatives of 1-(1-phenylcyclohexyl)piperidine (phencyclidine, PCP) were synthesized: o-, m-, and p-phenols of PCP, 1-(1-phenylcyclohexyl)-4-piperidinol, and two stereoisomeric pairs of 3-phenyl-3-(1-piperidinyl)cyclohexanol and 4-phenyl-4-(1-piperidinyl)cyclohexanol. Inhibition of specific binding of tritiated PCP, morphine, or quinuclidinyl benzylate (QNB) in rat brain homogenates was measured for these compounds. Inhibition of PCP binding for selected compounds correlated with mouse rotarod assay activity. The most characteristic effects of hydroxylation of PCP on the cyclohexyl, piperidine, or phenyl moieties are the following: (i) it generally decreases its activity in inhibiting [3H]PCP binding by a factor of 10 to 80; (ii) it does not produce a large variation in the affinity for the morphine receptor; (iii) it produces a considerable decrease of the affinity for the muscarinic receptor. An important exception to these general observations was the metaphenolic derivative of PCP. This PCP derivative has an affinity for the [3H]PCP binding sites that is 8 times higher than that of PCP itself; its affinity for the muscarinic receptor is only twice lower than that of PCP, but its affinity for the morphine receptor is 430 times higher than that of PCP and only one order of magnitude lower than that of morphine itself.
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PMID:Chemical synthesis and molecular pharmacology of hydroxylated 1-(1-phenylcyclohexyl-piperidine derivatives. 627 47

[3H]-Phencyclidine (PCP) hydrochloride was given in intravenous (0.1 or 1 mg) or oral (1 mg) doses to male subjects. After 1 mg IV, drug and metabolites were recovered in urine (72.8 +/- 4.0% of dose), feces (4.7 +/- 0.9%), and perspiration. Fecal excretion was low (3.4 +/- 0.4%) after oral dosing and oral bioavailability was estimated at 72%. PCP comprised 16% of urinary radioactivity with 31% consisting of enzymatically hydrolyzable conjugates of hydroxylated metabolites. Both cis and trans isomers of 4-phenyl-4-(1-piperidinyl)cyclohexanol were found. Maximum average plasma PCP concentrations of 2.7 to 2.9 ng/ml were observed after oral and intravenous 1-mg doses. Blood/plasma ratios were approximately 1.0 and plasma binding was about 65%. Parent drug was found in saliva. Apparent terminal phase half-lifes averaged 21 +/- 3 hr (harmonic mean 17 hr, range 7 to 46 hr). The volume of distribution averaged 6.2 +/- 0.3 l/kg. Renal clearances were variable, but the average was 9% of the total clearance. Thus, PCP is cleared principally by metabolism.
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PMID:Phencyclidine disposition after intravenous and oral doses. 707 11

A GLC assay for phencyclidine (PCP) is described, which also simultaneously measures three primary hydroxylated metabolites formed from incubating PCP in tissue homogenates. Using the FID detector, the limits of reliable detection of PCP and both monohydroxy metabolites, 4-phenyl-4-piperidino-cyclohexanol, 2, and 1-(1-phenylcyclohexyl)-4-hydroxypiperidine, 3, are 0.02 mumol per injection and 0.05 mumol for the dihydroxy metabolite, 4-(4'-hydroxypiperidino)-4-phenylcyclohexanol, 2A. Baseline separation of an compounds was achieved and coefficients of variation (between-run) was 3-6% for PCP, and both monohydroxy metabolites, and 12% for the dihydroxy metabolite. A GCMS assay is also reported herein for the analysis of PCP at low levels, and can detect 5 pmol per injection of PCP, with a linear standard curve from 50 to 2000 pmol.
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PMID:A gas-liquid chromatography assay for phencyclidine and its metabolites. 720 59

To elucidate the biological activity of natural metabolites of phencyclidine (PCP), we examined the behavioral effects of a major metabolite, the trans isomer of 4-phenyl-4-(1-piperidinyl)cyclohexanol [(trans)PPC], in mice, (Trans)PPC caused dose-related increase in locomotor activity and rearing in mice when injected intraperitoneally at the doses ranging from 10 to 30 mg/kg. (Trans)PPC at any dose tested failed to produce swaying and falling. On the other hand, PCP at the doses ranging from 1 to 10 mg/kg caused swaying and falling as well as hyperlocomotion in a dose-related manner. These indicate that unlike PCP, hyperlocomotion and rearing may be the predominant behavioral responses to (trans)PPC in the 10-30 mg/kg dose range. Furthermore, it is feasible to surmise that not only PCP but also its major metabolite (trans)PPC is involved in psychotic reactions produced by PCP.
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PMID:Behavioral effects of phencyclidine and its major metabolite, (trans)4-phenyl-4-(1-piperidinyl)cyclohexanol, in mice. 788 Apr 57

The major metabolite of phencyclidine (PCP), the trans isomer of 4-phenyl-4-(1-piperidinyl)cyclohexanol [(trans)-4-PPC], inhibited [3H]N-(1-(2-thienyl)cyclohexyl)-3,4-piperidine ([3H]TCP) binding to well-washed rat cortical membranes with much less activity than PCP itself. In contrast, it inhibited [3H]dopamine ([3H]DA) uptake in rat striatal synaptosomes to a similar extent as PCP. Considering our previous observations that intraperitoneally administered (trans)-4-PPC elicits dose-related increases in locomotor activity and rearing in mice, (trans)-4-PPC as well as PCP may be involved in psychotomimetic effects of PCP due to its inhibitory effect on DA uptake.
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PMID:Effects of the major metabolite of phencyclidine, the trans isomer of 4-phenyl-4-(1-piperidinyl)cyclohexanol, on [3H]N-(1-[2-thienyl] cyclohexyl)-3,4-piperidine ([3H]TCP) binding and [3H]dopamine uptake in the rat brain. 789 76

The incorporation of phencyclidine(PCP) and its three major hydroxylated metabolites, 1-(1-phenylcyclohexyl)-4-hydroxypiperidine(PCHP), trans-4-phenyl-4-piperidinocyclohexanol(t-PPC) and trans-1-phenyl-1-(4'-hydroxypiperidino)-4-cyclohexanol(t-PCPdiol) into rat hair was studied. Three Dark Agouti male rats were intraperitoneally administered with PCP x HCl at a dose of 0.5 or 1.0 mg/kg once a day for 10 successive days. The plasma samples were collected from 5 min to 360 min after injection of each drug. The hair samples were collected 28 days after the first administration. The hair samples were extracted with methanol-5N hydrochloric acid(20:1) for 1 h under sonication. The plasma and hair extracts were extracted or purified with Bond Elut Certify and the extracts were silylated for the determination of PCP and its metabolites by GC/MS. The plasma AUCs were as follows; PCP(2.03 microg x min/ml) > t-PCPdiol(0.60 microg x min/ml) > PCHP(0.11 microg x min/ml) > t-PPC (0.065 microg x min/ml), while the hair concentrations were as follows; PCP(7.51 ng/mg) > PCHP (1.22 ng/mg) > t-PPC(0.10 ng/mg) > t-PCPdiol (0.05 ng/mg). In view of their AUCs, the hair concentration of t-PCPdiol was quite low, whereas that of PCP was so high. PCHP, t-PPC or t-PCPdiol was separately administered as the parent drug to the rats, and then the plasma and hair samples were analyzed in the same manner as PCP experiments. The incorporation rates ([hair concentration]/[AUC]) of PCP and its hydroxylated metabolites were as follows; PCP(2.29) > PCHP(0.79) > t-PPC(0.36) > t-PCPdiol(0.32). These data suggest that the decrease in lipophilicity caused by the hydroxylation of PCP suppresses the incorporation of the metabolites from blood into hair and the hydroxylation on cyclohexane ring(t-PPC) induces the decrease of the drug incorporation into hair more than that on piperidine ring(PCHP).
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PMID:Incorporation of phencyclidine and its hydroxylated metabolites into hair. 946 69

We evaluated the usefulness of hair root analysis to diagnose acute phencyclidine (PCP) poisoning. Male rats were i.p. administered acute poisonous doses (80, 100 and 120 mg/kg) of PCP hydrochloride and the hair roots were plucked out with hair nippers at certain times after administration. The hair root samples were extracted with methanol/HCl. After evaporation of the solvent, the residue was derivatized with N,O-bis(trimethylsilyl) acetamide and analyzed with GC/MS. PCP was detected at high concentrations (up to 181.7 ng/mg) from all samples. The peak concentrations at every dose were observed at 6 h. The concentrations of PCP in the rat hair roots increased dose-dependently in the range of the doses. 1-(1-Phenylcyclohexyl)-4-hydroxypiperidine (PCHP) and trans-1-phenyl-1(4'-hydroxypiperidino)-4-cyclohexanol (t-PCPdiol) were also detected from 5 and 15 min to 48 h after administration, respectively. It is concluded that hair root is a useful specimen for the diagnosis of acute PCP poisoning because PCP, PCHP and t-PCPdiol are detected very soon after administration and a large amount of them is retained in hair root for a long time. PCHP was found from the early stage in hair roots and its concentration was higher than that of t-PCPdiol for 6 h. However, the concentration of t-PCPdiol became higher than that of PCHP after 6 h. These phenomena could be explained by the time lag of production of the primary (PCHP) and the secondary metabolite (PCPdiol).
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PMID:Evaluation of hair root analysis for acute phencyclidine poisoning and behavior of phencyclidine metabolites in rat hair root. 963


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