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E J Cone

Publications and source records attributed to E J Cone.

At least 145 records · Page 8Linked to original sources
PubMed1981

Simultaneous determination of phencyclidine and monohydroxylated metabolites in urine of man by gas chromatography-mass fragmentography with methane chemical ionization.

Phencyclidine and monohydroxy metabolites were measured in human urine using gas chromatography-mass fragmentography with methane chemical ionization. Samples were extracted either untreated or following acid hydrolysis, derivatized with heptafluorobutyric anhydride, separated on a 3% SE-30 column and analyzed by mass fragmentography. The assay was sensitive to ca. 0.01 microgram/ml for phencyclidine and ca. 0.05 microgram/ml for the metabolites. Urine samples from five human subjects enrolled in a methadone maintenance program who had ingested phencyclidine were analyzed. The phencyclidine concentration ranged from 0.3 to 23.7 microgram/ml. The concentrations of metabolites ranged from 0 to 1.8 microgram/ml. A new monohydroxy metabolite was detected in the samples, but its structure was not fully elucidated. The specificity of the assay was examined.

Gas Chromatography-Mass Spectrometry↗
PubMed1981

Phencyclidine metabolism: resolution, structure, and biological activity of the isomers of the hydroxy metabolite, 4-phenyl-4-(1-piperidinyl)cyclohexanol.

One of the major biotransformation pathways in the metabolism of phencyclidine is hydroxylation at C-4 of the cyclohexane ring to give 4-phenyl-4-(1-piperidinyl)cyclohexanol (1). Since the latter compound can exist as cis and trans isomers and the synthetic mixture has been reported to be biologically active, it was of interest to separate the isomers, test them for biological activity, and determine their ratio as metabolic products of phencyclidine. The synthetic mixture of 1 was separated by TLC and the individual isomers were characterized by 13C and 1H NMR and MS analyses. Preliminary testing of the isomers in the mouse rotarod assay indicates that the trans isomer (1b) is only slightly more active then the cis isomer (1a). Both isomers produced seizure activity and lethality at doses required to produce maximal ataxia.

Animals↗
PubMed1981

Structure-activity relationships of the cycloalkyl ring of phencyclidine.

In order to investigate the structural requirements for a cycloalkyl moiety in the potent hallucinogen 1-(1-phenylcyclohexyl)piperidine (PCP, 1), a series of structural analogues was synthesized in which the size of the cycloalkyl ring was varied from three carbons to eight carbons. Biological activities of these compounds were assessed in an in vitro assay (phencyclidine binding assay) and an in vivo assay (discriminative stimulus assay). As the cycloalkyl ring size decreased from that of cyclohexane (PCP), PCP-like activity declined in both assays, but as the cycloalkyl ring size became larger than cyclohexane, a sharp decline in PCP-like activity was observed in the in vivo assay, while activity in the in vitro assay was only slightly less than that of PCP. 1-(1-Phenylcyclooctyl)piperidine (8) had potent competitive binding properties in the in vitro binding assay but produced no observable PCP-like effects in the in vivo assay. The importance of the cycloalkyl ring in the structure of PCP was demonstrated by testing benzylpiperidine (2), which had almost no measurable activity in either assay.

Animals↗
PubMed1981

Physiologic effects and plasma kinetics of phenylethanolamine and its N-methyl homolog in the dog.

Single i.v. doses of the endogenous trace amine phenylethanolamine (PEOH) and its N-methyl homolog (NMPEOH) were administered to separate groups of five dogs. The dose- and time-related effects of these compounds were measured on pupillary diameter, heart rate and body temperature. Blood samples were obtained concurrently with the physiologic measures and plasma levels of PEOH and NMPEOH were determined by gas chromatography. Both compounds dilated pupils, decreased heart rate and tended to lower body temperature. NMPEOH was approximately 1.25 times more potent than PEOH in dilating pupils. The plasma pharmacokinetics of both PEOH and NMPEOH could be described by a biexponential function with half-lives for the elimination phase of approximately 30 to 60 min. Plasma levels correlated significantly with increases in pupil diameter for both drugs, but only plasma levels of NMPEOH correlated significantly with changes in heart rate or body temperature. The present findings demonstrate that the endogenous trace amine PEOH and its N-methyl homolog NMPEOH, which may be produced endogenously by the enzymatic action of phenylethanolamine-N-methyl-transferase, produce prominent physiologic effects when administered i.v. in the dog, thus suggesting they may have physiologic roles in mammalian nervous system function.

2-Hydroxyphenethylamine↗
PubMed1980

Fluorescence properties of pseudomorphine and congeners: structure-activity relationships.

The fluorescence properties of morphine congeners oxidized with potassium ferro-ferricyanide are described. Fluorescence did not occur in congeners with the following structural features: an alkyl or acyl group at the 3-O-position, a C-6 carbonyl group, or absence of the furan oxygen. Masking the carbonyl group by ethylene ketal formation effectively restored fluorescence. Morphine congeners that fluoresced were most sensitive to structural changes at C-6, C-7, anC-8. Details of effects of structural changes on emission maxima, intensity, and Stokes' shift are reported.

Molecular Conformation↗
PubMed1979

Comparative metabolism of codeine in man, rat, dog, guinea-pig and rabbit: identification of four new metabolites.

The metabolism and excretion of codeine and its metabolites in untreated urine of man, rat, dog, guinea-pig and rabbit have been examined. Metabolites were identified by gas chromatography mass spectrometry operated in the chemical ionization mode (methane). Concentrations of codeine and metabolites were measured by selected ion monitoring. Both codeine and norcodeine were detected in the urine of all species but a new metabolite, hydrocodone, was found only in the urine from man, guinea-pig and dog. Additional metabolites (presumably resulting from the metabolism of hydrocodone) were also detected in man and guinea-pig. Overall recoveries of drug and metabolites from untreated urine were low for all species.

Adult↗
PubMed1978

Simultaneous determination of hydromorphone, hydrocodone and their 6alpha- and 6beta-hydroxy metabolites in urine using selected ion recording with methane chemical ionization.

A selected ion recording using chemical ionization (methane) is described for the simultaneous measurement of hydrocodone, hydromorphone and their respective 6alpha- and 6beta-hydroxymetabolites in human urine. The samples were acid-hydrolyzed, extracted and derivatized by silylation. Only partial resolution of the components on 3% OV-17 was achieved but was sufficient for their determination. The [M+1]+ ions of the drugs and metabolites as well as the [M+29]+ ion of the internal standard were recorded. The assay was sensitive down to c. 0.01 microgram ml-1. The relative standard deviation of standards processed along with the samples ranged from 4.5-8.2%. Hydrocodone was found to be metabolized in man primarily by O-demethylation and 6-keto reduction. Hydromorphone was excreted mainly in the unchanged form (after acid-hydrolysis) with only minor amounts of the 6-hydroxymetabolites being detected. A lack of stereoselectivity in the metabolic reduction ofhydrocodone was observed.

Codeine↗
PubMed1978

The metabolism of azidomorphine in a human subject.

1. The metabolism of azidomorphine, a potent narcotic analgesic, was studied in a human subject who had received a single 1.8 mg dose subcutaneously. 2. Azidomorphine was excreted in the urine in small amounts as the intact drug and as a metabolite, 6-deoxy-6beta-aminodihydromorphine. Larger amounts of conjugated azidomorphine also were detected. 3. The azido group of azidomorphine was relatively stable towards enzymic and chemical change.

Adult↗
PubMed1978

The identification and measurement of two new metabolites of naltrexone in human urine.

Two metabolites of naltrexone were identified in human and rat urine following drug administration. The metabolites, 2-hydroxy-3-0-methylnatrexone and 2-hydroxy-3-0-methyl-6 beta-naltrexol, were identified by comparison of their respective gas chromatographic retention times and methane chemical ionization spectral patterns with authentic standards. The standards were obtained by chemical synthesis from naltrexone. Urinary excretion of the two metabolites was measured by single ion recording of the pseudomolecular ions of the metabolites and an internal standard. Excretion data was collected from 5 human subjects over a period of 5 days following a single dose of naltrexone. The metabolites, 2-hydroxy-3-0-methylnatrexone and 2-hydroxy-3-0-methyl-6 beta-natrexol were found to account for an average (+/- standard error) of 0.45 +/- 0.08% and 4.6 +/- 2.1% of the administered dose, respectively. An unusually long half-life of elimination of the latter metabolite (mean of 20.2 +/- 1.8 hr) was observed. Acid-hydrolysis of the samples failed to produce a significant increase of either metabolite indicating that the major protion of these metabolites is excreted in the free form.

Animals↗
PubMed1978

Concentrations of phenethylamine in dog following single doses and during intravenous self-administration.

A gas chromatographic procedure is described which was used to measure concentrations of beta-phenethylamine (PEA) in dog plasma following single or multiple infusions. Plasma levels were determined immediately following drug infusions during PEA self-administration sessions. At a unit dose of 3 mg/kg/infusion the concentration of PEA ranged from 1 to 3.95 microgram/ml of plasma, and from 2.5 to 4.75 microgram/ml at a unit dose of 6 mg/kg/infusion. At the time of responding for another infusion the plasma concentration varied between 0.16 and 0.52 microgram/ml and between 0.08 and 0.26 microgram/ml, for the two doses, respectively. Whole-body concentrations of PEA during self-administration were estimated according to a one compartment, open model using experimentally determined plasma half-lives obtained from single dose studies and inter-infusion intervals. Relatively little accumulation of PEA was predicted according to this model which correlated well with the experimental data. During the course of a self-administration session plasma levels rose initially following the infusion and declined to relatively constant levels ("response concentrations") when a subsequent drug-seeking response was made. Significant differences in "response concentrations" were observed between dogs and between doses. It is suggested that this response pattern is related to the distribution and clearance rate of the drug from plasma and well-perfused tissues.

Animals↗
PubMed1977

Urinary excretion of hydromorphone and metabolites in humans, rats, dogs, guinea pigs, and rabbits.

Hydromorphone was administered as a single dose to humans, rats, dogs, guinea pigs, and rabbits, and timed urinary collections were made. GLC-mass spectrometric and GLC analyses of the samples revealed the presence of the parent compound and both 6-hydroxy epimers as metabolites in the urine of all species. Free or conjugated parent drug predominated, while levels of free or conjugated 6beta-hydroxy metabolite were higher than or equal to those of the 6alpha-form. The time courses of excretion of drug and metabolites were similar for all species, with the major portion being excreted in the first 24 hr. Generally, free and conjugated drug were undetectable in human urine after 8 and 48 hr, respectively.

Adult↗
PubMed1976

General procedure for the isolation and identification of 6-alpha- and 6-beta-hydroxy metabolites of narcotic agonists and antagonists with a hydromorphone structure.

In order to aid in the elucidation of the metabolism of drugs containing the hydromorphone structure, a method is described for isolation from urine, separation and identification of the 6-alpha- and 6-beta-hydroxy metabolites. The samples were acid-hydrolyzed, extracted, and separated by thin-layer chromatography. The zone containing the hydroxy metabolites was removed and the compounds were re-extracted and analyzed by gas-liquid chromatography (GLC). Silylation of the extract was necessary in most cases for optimum GLC resolution of the alpha- and beta-hydroxy epimers. To demonstrate application of this method, the urine of guinea-pigs and rats which had received a single 40-mg dose of naloxone subcutaneously was analyzed. Analysis indicated a alpha/beta ratio of 0.41 for the guinea-pig. In contrast, the amount of 6-alpha-naloxol found in the urine of the rat was negligible in comparison with the 6-beta-hydroxy metabolite, indicating a species difference in the stereospecificity of the drug-metabolizing enzyme.

Animals↗
PubMed1975

Biosynthesis, isolation, and identification of 6-beta-hydroxynaltrexone, a major human metabolite of naltrexone.

Chemical reduction of naltrexone is described in an attempt to synthesize 6-beta-hydroxynaltrexone. Only the epimer, 6-alpha-hydroxynaltrexone, was produced. Pilot metabolic studies on naltrexone in the dog, rat, and guinea pig were made to determine which animal produced the greatest amount of 6-beta-hydroxynaltrexone. The guinea pig was selected and used to produce the metabolite. Isolation and purification methods are described, and spectral data are presented for structural confirmation of the metabolite.

Animals↗