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)

Fifty patients with P. carinii pneumonitis were randomized to receive either pentamidine isethionate or trimethoprim-sulfamethoxazole therapy. Those not responding favorably to the first drug after three or more days of therapy were changed to the alternate drug. Of the 26 patients initially treated with TMP-SMZ, 20 recovered (0.77)-17 after TMP-SMZ alone and three of nine who were crossed over to pentamidine. Of the 24 patients initially treated with pentamidine, 18 recovered (0.75)-14 of 15 who received only pentamidine and four of nine who were crossed over to TMP-SMZ. Abnormal values for blood urea nitrogen, creatinine, or glucose; inflammation at injection sites; or combination of these effects occurred in 14 of the 15 patients treated with pentamidine alone. Only one of the 17 patients treated with TMP-SMZ alone developed any of these abnormalities. This study shows that TMP-SMZ is as effective as pentamidine in the treatment of PCP, and that it offers the advantages of minimal adverse effects, oral administration, and ready availability.
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PMID:Comparison of pentamidine isethionate and trimethoprim-sulfamethoxazole in the treatment of Pneumocystis carinii pneumonia. 30 78

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

Displacement of [3H]MK-801 (dizocilpine, 1) binding to rat brain membranes has been used to evaluate the affinities of novel dibenzocycloalkenimines related to 1 for the ion channel binding site (also known as the phencyclidine or PCP receptor) on the N-methyl-D-aspartate (NMDA) subtype of excitory amino acid receptor. In common with many other agents having actions in the central nervous system, these compounds contain a hydrophobic aromatic moiety and a basic nitrogen atom. The conformational rigidity of these ligands provides a unique opportunity to evaluate the importance of specific geometrical properties that influence active-site recognition, in particular the role of the nitrogen atom in hydrogen-bonding interactions. The relative affinities (IC50s) of hydrocarbon-substituted analogues of 1 and ring homologated cyclooctenimines illustrate the importance of size-limited hydrophobic binding of both aryl rings and of the quaternary C-5 methyl group. Analysis of the binding of a series of the 10 available structurally rigid dibenzoazabicyclo[x.y.z]alkanes, by using molecular modeling techniques, uncovered a highly significant correlation between affinity and a proposed ligand-active site hydrogen bonding vector (r = 0.950, p less than 0.001). These results are used to generate a pharmacophore of the MK-801 recognition site/PCP receptor, which accounts for the binding of all of the known ligands.
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PMID:Role of hydrogen bonding in ligand interaction with the N-methyl-D-aspartate receptor ion channel. 169 88

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

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.
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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

Computer-assisted molecular modelling techniques have been employed to develop receptor models for the phencyclidine (PCP) and sigma binding sites. The models differ in the position of the nitrogen atom, direction of the nitrogen-lone pair vector and in the location and nature of secondary binding groups. This study predicts the existence of distinct receptors for sigma and PCP ligands, and our receptor models can be used to design and predict the activity of drugs with PCP and/or sigma activity.
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PMID:Quantitative conformational analyses predict distinct receptor sites for PCP-like and sigma drugs. 283 Jan 25

Computer-assisted molecular modelling techniques and electrostatic analyses of a wide range of phenycyclidine (PCP) and sigma ligands, in conjunction with radioreceptor studies, were used to determine the topographies of the PCP and sigma receptors. The PCP receptor model was defined using key molecules from the arylcyclohexylamine, benzomorphan, bridged benz[f]isoquinoline, and dibenzocycloalkenimine drug classes. Hypothetical receptor points (R1, R2) were constructed onto the aromatic ring of each compound to represent hydrophobic interactions with the receptor, along with an additional receptor point (R3) representing a hydrogen bond between the nitrogen atom and the receptor. The superimposition of these key molecules gave the coordinates of the receptor points and nitrogen defining the primary PCP pharmacophore as follows: R1 (0.00, 3.50, 0.00), R2 (0.00, -3.50, 0.00), R3 (6.66, -1.13, 0.00), and N (3.90, -1.46, -0.32). Additional analyses were used to describe secondary binding sites for an additional hydrogen bonding site and two lipophilic clefts. Similarly, the sigma receptor model was constructed from ligands of the benzomorphan, octahydrobenzo[f]quinoline, phenylpiperidine, and diphenylguanidine drug classes. Coordinates for the primary sigma pharmacophore are as follows: R1 (0.00, 3.50, 0.00), R2 (0.00, -3.50, 0.00), R3 (6.09, 2.09, 0.00), and N (4.9, -0.12, -1.25). Secondary binding sites for sigma ligands were proposed for the interaction of aromatic ring substituents and large N-substituted lipophilic groups with the receptor. The sigma receptor model differs from the PCP model in the position of nitrogen atom, direction of the nitrogen lone pair vector, and secondary sigma binding sites. This study has thus demonstrated that the differing quantitative structure-activity relationships of PCP and sigma ligands allow the definition of discrete receptors. These models may be used in conjunction with rational drug design techniques to design novel PCP and sigma ligands of high selectivity and potency.
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PMID:Receptor site topographies for phencyclidine-like and sigma drugs: predictions from quantitative conformational, electrostatic potential, and radioreceptor analyses. 284 51

The low energy conformation of MK801. (+)-N-allyl-N-normetazocine, dexoxadrol, etoxadrol and ketamine was found to possess the unique pharmacophore geometry of a PCP pharmacophore hypothesis recently reported by Carroll et al. (1988). Moreover, the union of the volumes of these compounds in their proposed receptor bound conformation locked together such that equivalent groups were superimposed showed that none of the compounds extended into the binding site volume above and below the aromatic ring and along the nitrogen vector.
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PMID:Phencyclidine (PCP) and phencyclidine-like compounds: a molecular graphics-molecular mechanics study. 285 51

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 sensitive and specific assay for the quantitation of phencyclidine (PCP), its several metabolites, and derivatives in biological samples is described. The method is based on the extraction of PCP and related compounds with organic solvents followed by gas chromatographic (GC) separation with nitrogen-phosphorous (NP) detection of the extract derivatized with heptafluorobutyric anhydride. The detection limit was about 5 pmol per injection with a linear standard curve to 16 nmol in the initial sample. The recovery of different compounds ranged from 80 to 98%. Precision of the method was within 3 to 5%, while day-to-day variations did not exceed 5%. The present procedure permits the identification and quantitation of PCP and its major primary and secondary metabolites. In addition, several PCP analogs and derivatives that are not recognized as PCP metabolites can be quantitated using this procedure. The assay was applied for the quantitation of PCP and its metabolites in tissue homogenates and body fluids of PCP-dosed animals as well as in the urine of PCP-intoxicated humans. An in vitro system for PCP biotransformation studies by liver and placental microsomes was also developed.
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PMID:Quantitation of phencyclidine, its metabolites, and derivatives by gas chromatography with nitrogen-phosphorus detection: application for in vivo and in vitro biotransformation studies. 372 69


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