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)

1. The metabolism of phencyclidine (PCP) and three congeners, differing in the structure of the amine moiety, by liver microsomes from phenobarbital-pretreated rats, was determined. 2. The metabolites generated by sequential oxidation of the two carbons alpha to the nitrogen were measured for PCP and its diethyl analogue (PCDE). 3. Alpha hydroxylation was a dominant metabolic pathway for PCDE, but less so for PCP. 4. Evaluation of affinities for the N-methyl-D-aspartate (NMDA) and sigma receptors in vitro showed that the product of alpha-hydroxylation of PCDE, phenylcyclohexylethylamine (PCE), was very potent. 5. Therefore, the in vivo actions of PCDE could include a significant contribution by PCE. 6. All congeners formed phenylcyclohexylamine (PCA), the product of a second alpha-hydroxylation, with PCDE and the pyrrolidine analogue generating the largest proportion.
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PMID:The alpha carbon oxidation of some phencyclidine analogues by rat tissue and its pharmacological implications. 217 Dec 33

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)
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PMID:Discriminable effects of phencyclidine analogs evaluated by multiple drug (PCP versus OTHER) discrimination training. 249 47

The synthesis and in vitro sigma receptor activity of the two diastereomers of U50,488 [(+/-)-2], namely, (1R,2S)-(+)- cis-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacet ami de [(+)-1] and (1S,2R)-(-)-cis-3,4-dichloro- N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide [(-)-1], are described. (+)-1 and (-)-1 were synthesized from (+/-)-trans-N-methyl-2-aminocyclohexanol [(+/-)-3]. Pyridinium chlorochromate (PCC) oxidation of the N-t-Boc-protected derivative of (+/-)-3 afforded (+/-)-2-[N- [(tert-butyloxy)carbonyl]-N-methylamino]cyclohexanone [(+/-)-5]. The sequence of enamine formation with pyrrolidine, catalytic reduction, N-deprotection, and optical resolution afforded (1R,2S)-(-)-cis-2-pyrrolidinyl-N-methylcyclohexylamine [(-)-10] and (1S,2R)-(+)-cis-2-pyrrolidinyl-N-methylcyclohexylamine [(+)-10]. The optical purity (greater than 99.5%) of (-)-10 and (+)-10 was determined by HPLC analysis of the diastereomeric ureas formed by reaction with optically pure (R)-alpha-methylbenzyl isocyanate. The absolute configuration of (-)-10 and (+)-10 was determined by single-crystal X-ray diffractometry of the bis-(R)-mandelate salt. Condensation of optically pure (-)-10 and (+)-10 with 3,4-dichlorophenylacetic acid furnished (+)-1 and (-)-1, respectively. Compounds (+)-1, (-)-1, (-)-2, and (+)-2 were compared for their binding affinities at kappa opioid, sigma, D2-dopamine, and phencyclidine (PCP) receptors in competitive binding assays using [3H]bremazocine ([3H]BREM) or [3H]U69,593, [3H]-(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [[3H]-(+)-3-PPP], or [3H]-1,3-di(o-tolyl)guanidine ([3H]DTG), [3H]-(-)-sulpiride [[3H]-(-)SULP], and [3H]-1- [1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP), respectively. In the systems examined, (-)-2 exhibited the highest affinity for kappa receptors, with a Ki of 44 +/- 8 nM. However, (-)-2 also showed moderate affinity for sigma receptors, with a Ki of 594 +/- 3 nM [[3H]-(+)-3-PPP]. The (1R,2R)-(+)-enantiomer, (+)-2, had low affinity for both kappa and sigma receptors, exhibiting Ki values of 1298 +/- 49 nM at kappa ([3H]BREM) and 1270 +/- 168 nM at sigma [[3H]-(+)-3-PPP]. In contrast, the chiral cis compounds (+)-1 and (-)-1 showed high affinity for sigma receptors and negligible affinity for kappa opioid receptors in the [3H]BREM assay. Compound (-)-1 exhibited a Ki of 81 +/- 13 nM at sigma receptors [[3H]-(+)-3-PPP] and 250 +/- 8 nM ([3H]DTG).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Alterations in the stereochemistry of the kappa-selective opioid agonist U50,488 result in high-affinity sigma ligands. 254 74

Three homologues of 1-(1-phenylcyclohexyl)piperidine (PCP) containing the five-, six-, and seven-membered heterocyclic ring (1-(1-phenylcyclohexyl)pyrrolidine (PCPY), PCP, 1-(1-phenylcyclohexyl)hexamethyleneimine (PCHMI) were preincubated with microsomes from phenobarbital-induced rabbit liver. The microsomes were then diluted, an additional charge of NADPH was added, and N-demethylation of benzphetamine was determined. Preincubation of the microsomes with the analogues lowered P-450-dependent N-demethylation by a process that was NADPH-dependent, reduced CO binding to microsomes, and followed pseudo-first order kinetics. The relative rates of inactivation, PCP greater than or equal to PCPY greater than PCHMI, agreed with the order of inhibition of CO binding to reduced microsomes. This mechanism-based inhibition was not observed with phenylcyclohexylamine, indicating that the substituted nitrogen is necessary. The substituted nitrogen must also be part of a heterocyclic ring since the diethylamino analogue of PCP did not exhibit the same type of inhibition a heterocyclic ring is involved. These trends correlated with the expected relative stabilities of the cyclic form of the carbinolamine suggesting that the inhibitory species was formed from the closed ring isomer.
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PMID:Mechanism-based inhibition of cytochrome P-450 by heterocyclic analogues of phencyclidine. 289 81

A series of phencyclidine (PCP) related analogs, carbonitrile synthetic precursors and two monohydroxylated metabolites were compared pharmacologically in mice for their ability to produce ataxia using the rotarod method and toxicologically for their acute 4-hr lethality. The slope of the PCP dose-ataxic response curve was steeper than those of diazepam, pentobarbital, morphine and ketocyclazocine but not the slope of the sigma agonist, N-allylnormetazocine curve. Responses for all analogs, metabolites and precursors produced curves parallel to that of PCP. Ataxia potencies of all PCP-related compounds ranged from 0.05 to 2.15 X PCP and durations of action ranged from 18 to 65 min. N-ethyl-1-phenylcyclohexylamine, 1-[1-(2-thienyl)-cyclohexyl]-piperidine and 1-[1-(2-thienyl)-cyclohexyl]-pyrrolidine were most potent and least potent were 1-(1-phenyl-cyclohexyl)-4-methylpiperidine, the phenyl and thienyl morpholines and 4-phenyl-4-piperidinocyclohexanol. Among the PCP analogs, modifying the piperidine or aromatic ring effected changes only in potency. Seizures and respiratory depression characterized the lethal effects of PCP, its analogs, metabolites and precursors. However, the precursors failed to elicit the stereotyped movements and hyperactivity that preceded seizures produced by the other compounds. Overall potencies for lethality relative to PCP covered a narrow range (0.16-1.83) with the carbonitrile precursors being most potent. Therapeutic indices indicated relatively large margins of safety for 1-[1-(2-thienyl)-cyclohexyl]-piperidine, 1-[1-(2-thienyl)-cyclohexyl]-piperidine, N-ethyl-1-phenylcyclohexylamine and ketamine and the smallest were for 1-(1-phenylcyclohexyl)-4-methylpiperidine, the metabolite 4-phenyl-4-piperidinocyclohexanol and the three precursors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phencyclidine analogs and precursors: rotarod and lethal dose studies in the mouse. 674 25

Squirrel monkeys were trained to discriminate 0.16 mg/kg of 1-(1-phenylcyclohexyl) piperidine (PCP) from saline in a two-lever drug discrimination task on a fixed-ratio 32 schedule of food presentation. Intramuscular injections were given 5 min pre-session in a double alternation pattern. After reliable discriminative control of lever choice was established, dose-response determinations for generalization to the training dose of PCP was made with several doses of PCP, N-ethyl-1-phenylcyclohexylamine (PCE), 1-[1-(2-thienyl)cyclohexyl] piperidine (TCP), 1-(1-phenylcyclohexyl) morpholine (PCM), 1-(1-phenylcyclohexyl) pyrrolidine (PHP), and ketamine. All drugs produced dose-dependent PCP-appropriate responding. For each analogue, a dose was found which produced stimulus control of responding comparable to that of the PCP training dose. ED50 values were determined for each drug for percent drug-lever appropriate responding and for suppression of operant responding during test sessions. The relative potency for producing drug-lever appropriate responding was: TCP greater than PCP = PCE greater than PHP greater than PCM greater than ketamine. The relative potency for suppression of operant responding was: PCP = TCP greater than PHP greater than PCE greater than PCM greater than ketamine. In all cases, the dose necessary to suppress operant responding to fifty percent of vehicle rates was three to five times larger than the ED50 dose for drug-lever appropriate responding. The results of this study indicate marked similarities in the behavioral effects of these six arylcyclohexylamines.
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PMID:Discriminative stimulus properties of phencyclidine and five analogues in the squirrel monkey. 720 60

The 5-HT(7) receptor is targeted by several new antipsychotics such as clozapine and risperidone. We studied the effect of R-(+)-1-(toluene-3-sulfonyl)-2-[2-(4-methylpiperidin-1-yl)ethyl]-pyrrolidine (SB-258741), a specific 5-HT(7) receptor antagonist, in three models for positive symptoms, D-amphetamine-induced hyperactivity and D-amphetamine- and phencyclidine (PCP)-disrupted prepulse inhibition (PPI) in rats, with the aim of investigating the role of this receptor in the clinical effect of antipsychotics. We also tested this compound in a model for negative symptoms, PCP-disrupted social interaction (SIT) in rats. Induction of side effects by this compound was evaluated by testing its potency to reduce spontaneous motility and to induce catalepsy in rats. The effect of SB-258741 was compared to risperidone in all models. This study showed that SB-258741 had no beneficial effect on PCP-disrupted SIT. SB-258741 did not reverse D-amphetamine-disrupted PPI; however, it dose-dependently normalised PCP-disrupted PPI. SB-258741 antagonised D-amphetamine-induced hyperactivity but reduced motility of rats at similar doses. Thus, this specific 5-HT(7) receptor antagonist brought a clear positive outcome in only one model for positive symptoms of schizophrenia and had no beneficial effect in the model for negative symptoms. Consequently, it is clear that SB-258741 affects the PPI phenomenon but is not expected to have an antipsychotic effect on its own in clinic.
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PMID:Effects of the 5-HT(7) receptor antagonist SB-258741 in animal models for schizophrenia. 1188 57

The role of 5-hydroxytryptamine (serotonin) (5-HT)(7) receptor antagonism in the actions of atypical antipsychotic drugs (APDs), e.g., amisulpride, clozapine, and lurasidone, if any, is uncertain. We examined the ability of 5-HT(7) receptor antagonism alone and as a component of amisulpride and lurasidone to reverse deficits in rat novel object recognition (NOR) produced by subchronic treatment with the N-methyl-D-aspartate receptor antagonist phencyclidine (PCP), and we examined the ability of supplemental 5-HT(7) antagonism to augment the inability of sulpiride, haloperidol, and (1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY379268), a metabotropic glutamate receptor (mGluR) 2/3 agonist, which lack 5-HT(7) antagonism, to reverse the NOR deficit. The 5-HT(7) receptor antagonist, (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine (SB269970) (0.1-1 mg/kg) dose-dependently reversed PCP-induced NOR deficits. In addition, the ability of lurasidone (0.1 mg/kg) and amisulpride (3 mg/kg) to reverse this deficit was blocked by cotreatment with the 5-HT(7) receptor agonist (2S)-(+)-5-(1,3,5-trimethylpyrazol-4-yl)-2-(dimethylamino)tetralin (AS19) (5-10 mg/kg), which did not affect NOR in naive rats. Sulpiride, a less potent 5-HT(7) antagonist than amisulpride, did not itself improve the PCP-induced NOR deficit. However, a subeffective dose of SB269970 (0.1 mg/kg) in combination with subeffective doses of lurasidone (0.03 mg/kg), amisulpride (1 mg/kg), or sulpiride (20 mg/kg), also reversed the PCP-induced NOR deficit. Pimavanserin, a 5-HT(2A) inverse agonist, LY379268, and haloperidol did not potentiate the ability of subeffective SB269970 to improve the NOR deficit. Furthermore, the mGluR2/3 antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl)propanoic acid (LY341495), which blocks the effect of clozapine to reverse the NOR deficit, did not block the SB269970-induced amelioration of the NOR deficit. These results suggest 5-HT(7) antagonism may contribute to the efficacy of some atypical APDs in the treatment of cognitive impairment in schizophrenia and may itself have some benefit in this regard.
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PMID:The role of 5-hydroxytryptamine 7 receptors in the phencyclidine-induced novel object recognition deficit in rats. 2155 35

N-Methyl-D-aspartate (NMDA) receptor (NMDAR) hypofunction has been postulated to contribute to the cognitive deficit of schizophrenia. In this study, we examined the effect of lurasidone (Latuda; Dainippon Sumitomo Pharma Co. Ltd., Tokyo, Japan), a newly approved atypical antipsychotic drug (APD), on NMDAR synaptic function in rat frontal cortical pyramidal neurons. In vivo administration of lurasidone produced a significant and selective enhancement of NMDAR-mediated synaptic responses and surface expression of NR2A and NR2B subunits. Lurasidone has high affinity for serotonin 5-HT(1A), 5-HT(2A), and 5-HT(7) receptors and dopamine D(2) receptors. In vivo administration of the 5-HT(7) receptor antagonist (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2 -(2-(4-methyl-1-piperidinyl)ethyl)pyrrolidine (SB-269970) mimicked the enhancing effect of lurasidone on NMDAR responses, whereas the D(2) receptor antagonist haloperidol failed to do so. Previous studies have found that short-term administration of lurasidone reverses the cognitive impairment induced by subchronic administration of phencyclidine (PCP), an NMDAR noncompetitive antagonist. In this study, we found that lurasidone, as well as the prototypical atypical APD clozapine, restored NMDAR-mediated synaptic responses to normal levels in the PCP model of schizophrenia. These results suggest that NMDAR is the potential key molecular target of lurasidone, possibility via antagonizing 5-HT(7) receptors, which is consistent with evidence that 5-HT(7) receptor antagonism contributes to cognitive enhancement by atypical APDs in patients with schizophrenia.
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PMID:The novel antipsychotic drug lurasidone enhances N-methyl-D-aspartate receptor-mediated synaptic responses. 2207 17

Classic examples of psychoactive arylcycloalkylamines include ketamine and 1-(1-phenylcyclohexyl)piperidine (PCP) and many others serve as important structural templates for neuropharmacological research. The recent emergence of PCP analogues that can be obtained from internet retailers requires the implementation of appropriate monitoring strategies for harm reduction purposes. Access to analytical data plays a key part when encountering these substances, especially if reference material is not available. The present study describes the synthesis of three substituted 1-(1-phenylcyclohexyl)piperidines, (3-MeO-, 4-MeO- and 3-Me-PCP) and three substituted 1-(1-phenylcyclohexyl)pyrrolidine analogues (3-MeO-, 4-MeO- and 3-Me-PCPy). Analytical characterizations of all six arylcyclohexylamines and their primary 1-phenylcyclohexanamine intermediates included gas chromatography ion trap electron- and chemical ionization and high resolution mass spectrometry, liquid chromatography electrospray hybrid triple-quadrupole linear ion trap tandem mass spectrometry, infrared, diode array detection and (1) H and (13) C nuclear magnetic resonance (NMR) spectroscopy. Solvent (CDCl3 vs. d6 -DMSO) and protonation effects (free bases vs hydrochloride salts) were studied in order to investigate the impact on shifts and splitting patterns, for example, when attempting to assign separate axial and equatorial proton chemical shifts of NMR spectra. Differentiation between the isomeric 3-MeO-/4-MeO-PCP and PCPy analogues was feasible under mass spectral conditions. Gas chromatography analysis appeared to induce notable degradation of the 4-MeO-substituted analytes, especially when dealing with the HCl salts which led to the detection of the substituted 1-phenylcyclohex-1-ene nucleus. This phenomenon was observed to be less pronounced with the 3-MeO isomers, possibly due to the resonance properties of the para-methoxy group followed by more facile elimination of the amine.
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PMID:Preparation and analytical characterization of 1-(1-phenylcyclohexyl)piperidine (PCP) and 1-(1-phenylcyclohexyl)pyrrolidine (PCPy) analogues. 2355 50


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