Syntheses of 3-O- and 6-O-propanoylmorphine--a reinvestigation and correction.

3-O-Propanoylmorphine was obtained using the conditions reported earlier for the specific synthesis of 6-O-propanoylmorphine. The latter isomer was synthesized using two different methods; the two compounds were authenticated using IR, MS, carbon-13 and proton NMR.

Antinociceptive activity of propionyl esters of morphine: a reevaluation.

The antinociceptive activity of the propionyl homologues of 3-O- and 6-O-acetyl- and 3,6-O-diacetylmorphine was re-investigated using materials of unequivocally established structure. Testing was in male Wistar rats at 60 min following subcutaneous administration by the rat tail-flick method. Results indicate that the antinociceptive activity of 3-O-propionylmorphine was similar to that of 3-O-acetylmorphine. 6-O-Propionylmorphine and 3,6-O-dipropionylmorphine had similar antinociceptive activity and, like 6-O-acetylmorphine, 6-O-propionylmorphine may be the pharmacologically active principle responsible for the antinociceptive activity of its disubstituted homologue.

Mouse hepatic metabolites of ketoconazole: isolation and structure elucidation.

Oxidation, cleavage and degradation of the imidazole and piperazine rings, O-dealkylation, and aromatic hydroxylation are the reported pathways of ketoconazole (KC) metabolism. Metabolites were examined in hepatic extracts from male Swiss Webster mice treated with KC (350 mg kg-1 po x 7 days) in a 0.25% gum tragacanth suspension at 10 ml kg-1. Livers were collected 24 h after the last dose and stored at -70 degrees C. A mixture of chloroform/methanol extracts of liver homogenates were dried under vacuum and methanol extracts of the residue were chromatographed by a series of preparative and analytical HPLC techniques. Structure assignments were made by NMR and MS/MS techniques. It was demonstrated that KC was biotransformed to a number of products. Nine were isolated and seven identified as exclusive products of the biotransformation of the 1-acetylpiperazine moiety of KC. This substituent was biotransformed to the following: piperazine (de-N-acetyl ketoconazole, DAKC), N-carbamylpiperazine, N-formylpiperazine, 2,3-piperazinedione, 2-formamidoethylamine, ethylenediamine and amine. The 1H-NMR and MS data suggested that the remaining two metabolites were products resulting from the oxidation of the imidazole ring.

Chiral identification and determination of ephedrine, pseudoephedrine, methamphetamine and methcathinone by gas chromatography and nuclear magnetic resonance.

The enantiomers of the related substances methamphetamine, ephedrine, pseudoephedrine and methcathinone were determined by both gas chromatography after derivatization and by nuclear magnetic resonance using a chiral solvating agent. For GC the substances were derivatized with (R)-(+)-alpha-methoxy-alpha-(trifluoromethyl)phenylacetic acid (MTPA) to give diasteromeric derivatives. Resolution (baseline) of at least 1.6 was obtained between all derivatives. NMR determination of the enantiomers was conducted in a chiral environment by the addition of the chiral solvating agent, (R)-(+)-1,1'-bi-2-naphthol, to NMR solutions of the substances. Racemization of methcathinone was demonstrated to be facile by exposure to alkaline solutions for varying periods of time. Enantiomeric ratios of some products derived from the oxidation of ephedrine were determined.

Identification of the N-methylated analogs of the hallucinogenic amphetamines and some isomers.

The drugs 2-, 3-, and 4-methoxy-N-methylamphetamine, 3-methoxy-4,5-methylenedioxy-N-methylamphetamine, and 3,4-methylenedioxy-N-methylamphetamine are identified by spectroscopic techniques. The ultraviolet and mass spectra of isomers are similar, but proton magnetic resonance and infrared spectra are distinctly different, and reference spectra and data are provided. Gas-liquid and thin layer chromatographic systems for the analysis are discussed.

Impurities in commercial saccharin. I. Impurities soluble in organic solvents.

Thirteen saccharin samples used for carcinogenicity tests in animals in various laboratories were analyzed for their chemical purity. Although most of the impurities were water-soluble, some were mainly soluble in organic solvents. These impurities were extracted with chloroform-methanol from a water solution of sodium saccharin. Samples obtained as acid-saccharin were converted to the sodium form before extraction. The major impurity in commercial saccharin, o-toluenesulfonamide, was also soluble in this system. Impurities were separated by gas-liquid chromatography of the underivatized, concentrated extract. Eleven major, well separated peaks were collected from the gas chromatographic column and identified by mass spectroscopy. Some of the peaks were compared with known standards. Qualitative and quantitative differences in impurities were observed among different saccharin samples. The identified impurities (in order of appearance from the gas-liquid chromatographic column) were as follows: o-toluenesulfonamide; p-toluenesufonamide; 1,2-benzisothiazole 1,1-dioxide; 1,2-benzisothiazoline 1,1-dioxide; diphenylsulfone; 0,0'-ditolylsulfone; o,m'-ditolylsulfone, o,p'-ditolylsulfone; m,p'-ditolylsulfone; p,p'-ditolylsulfone, and tetracosane.

"Designer" amphetamines: effects on behavior and monoamines with or without reserpine and/or alpha-methyl-para-tyrosine pretreatment.

Rats were given single injections of vehicle or one of three doses of (+)-amphetamine (AM), 4-methoxyamphetamine (MA) or 4-ethoxyamphetamine (EA) after pretreatment with vehicle or reserpine, and vehicle or alpha-methyl-para-tyrosine (AMPT). EA is a "designer" drug that was recently seized from an illicit laboratory in Canada. Locomotion of the rats was recorded after treatment with the drugs, and whole brain levels of the drugs as well as monoamine neurotransmitters and their major acidic metabolites were then determined. Neither of the ring-substituted AM analogues influenced locomotion. AM induced locomotion in a dose-dependent manner, and this effect was blocked by AMPT but potentiated by reserpine. Brain concentrations of EA were lower than those of the other two drugs. The brain levels of monoamines and their metabolites indicate that AM releases a newly synthesized pool of dopamine which is transferred to vesicles after re-uptake. A very low dose of AM, but not higher doses, was found to elevate serotonin (5-hydroxytryptamine: 5-HT) levels independently of effects on catecholamines. Both MA and EA affected monoamine metabolites in a manner consistent with actions as reversible inhibitors of monoamine oxidase-an effect which has been previously demonstrated to be true for MA. Both drugs increased 5-HT levels at a very low dose, as did AM, but also increased noradrenaline levels at this dose. It is concluded that EA is not a psychomotor stimulant, but is similar in many of its effects to MA, a potent hallucinogen.

Metabolic disposition of pyrazinamide in the rat: identification of a novel in vivo metabolite common to both rat and human.

Only limited studies have been reported on the disposition and pharmacokinetics of pyrazinamide (PZA) in both animals and humans. The metabolism of PZA has never been completely elucidated, consequently the metabolites of PZA, pyrazinoic acid (PA), 5-hydroxypyrazinoic acid (5-HOPA), and 5-hydroxypyrazinamide (5-HOPZA) were characterized and the disposition of PZA was examined following administration of 150 mg kg-1 of 14C-PZA to male Wistar rats. Comparable t1/2 for total radiolabel 14C (1.45 +/- 0.06 h) and PZA (1.39 +/- 0.04 h) in the blood compartment were observed. Cumulative 48 h excretion in urine and faeces accounted for 82.6 +/- 3.2 per cent and 11.0 +/- 1.3 per cent, respectively, of the dose administered. In the 0-6 h urine collections PA, 5-HOPA, 5-HOPZA, and PZA, respectively, accounted for 25.4 +/- 1.7, 17.7 +/- 1.2, 11.6 +/- 0.8, and 2.7 +/- 0.2 per cent of the administered dose. In the 6-12 h urine samples the proportions of PA and 5-HOPA increased statistically over the 0-6 h excretion whereas 5-HOPZA decreased. Administration of PZA to humans indicated 5-HOPZA was a major urinary metabolite in human. These data suggested that direct hydroxylation of PZA was an alternative pathway in the oxidation of PZA of importance to both human and rat.

Fungal metabolism of 4-substituted amphetamines.

1. rac.-4-Ethoxyamphetamine was incubated with 14 different yeast and fungal microorganisms. 4-Hydroxyamphetamine was the major metabolite; traces of N-acetyl-4-ethoxyamphetamine were also detected. 2. The major fungal (Cunninghamella) metabolite of 4-propoxyamphetamine and 4-benzyloxyamphetamine was 4-hydroxyamphetamine. The major metabolites of 4-methoxyamphetamine were N-acetyl-4-methoxyamphetamine and 4-hydroxyamphetamine. 3. Acetoin derivatives were formed when alkoxyamphetamine substrates were incubated in the presence of various fungi and yeasts. 4. The findings indicate that Cunninghamella echinulata may be a useful microbial model for drug disposition and interaction studies.