Studies in vivo and in vitro on N-acetylphenelzine.
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Biomedical subjects
Publications and source records attributed to G B Baker.
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A rapid, sensitive procedure for analysis of 2-phenylethylamine in brain tissue and urine is described. The method involves extraction with a liquid ion exchanger, elution with HCl, acetylation under aqueous conditions, pentafluorobenzoylation under anhydrous conditions and analysis using a gas chromatograph equipped with a capillary column and an electron-capture detector.
Mature male or female Sprague-Dawley rats were injected intraperitoneally with various doses (0.005, 0.027 and 0.05 mM/Kg) of (+) amphetamine sulfate or (+)-alpha-fluoromethyl-beta-phenylethylamine hydrochloride. Core (rectal) body temperatures were measured at pretreatment and 30, 60, 90, 120, 180, 240 and 300 minutes after treatment. Injection of (+)amphetamine resulted in increased body temperatures in all dose groups excepting males in the low dose (0.005 mM/kg) group after which temperatures returned to and remained at control levels. Injection of (+)alpha-fluoromethylphenylethylamine resulted in initially increased temperatures in all dose groups and at 180 minutes reduced temperatures in high dose males and in medium and high dose females. Hypothermia was not observed after treatment with (+)amphetamine. These results suggest that (+)alpha-fluoromethyl-beta-phenylethylamine has chemical properties distinct from those of (+)-amphetamine.
Groups of male Sprague-Dawley rats were injected acutely or chronically with tranylcypromine (10 mg/kg i.p.) or phenelzine (15 mg/kg i.p.) and extracts of their brains were analyzed by electron-capture gas chromatography for concentrations of p-tyramine. Concentrations of p-tyramine were significantly higher than control levels at all time intervals with both drugs, but these increases showed different patterns with each drug. With tranylcypromine treatment, para-tyramine levels peaked at day 2; with phenelzine treatment they increased steadily over the time course, surpassing levels obtained in tranylcypromine experiments by day 8.
The effects of tranylcypromine (TCP) HCl (4 mg/kg and 20 mg/kg i.p.) and phenelzine (PLZ) sulfate (10 mg/kg and 50 mg/kg) on levels of dopamine (DA), noradrenaline (NA), 5-hydroxytryptamine (5-HT), 3-methoxytyramine (3-MT) and normetanephrine (NM) in mesencephalon-pons, diencephalon, corpus striatum and hippocampus of rat brain were investigated. Effects of TCP on concentrations of DA and NA varied, depending on the brain area investigated and the dosage used. PLZ either had no effect or increased the concentration of DA and NA in the areas studied. Both drugs increased the concentrations of 3-MT and NM in areas where those metabolites could be measured. Both MAO inhibitors resulted in significant increases in 5-HT in all areas studied.
A series of (+) and (-) tetrahydro-beta-carboline-3-carboxamide stereoisomers related to the ethyl ester of beta-carboline-3-carboxylate (beta-CCE) have been tested for their ability to displace 3H-flunitrazepam from binding sites prepared from rat cerebral cortex (benzodiazepine receptors). The (+) stereoisomers of ethyl and propyl 1,2,3,4-tetrahydro-beta-carboline-3-carboxamides were the most potent inhibitors of specific 3H-flunitrazepam binding and had significantly lower IC50s than the corresponding (-) isomers. Although the IC50 values for this series of tetrahydro-beta-carboline-3-carboxamides were about 1000 fold higher than the IC50 value for beta-CCE, these compounds were as potent as the beta-carboline alkaloids harmane and harmine. The title compounds may be useful stereoisomeric probes for the characterization of subtypes of specific benzodiazepine binding sites.
Three N-alkylated analogues of amphetamine were administered intraperitoneally to male Sprague-Dawley rats and whole brain levels of amphetamine (AM) and the N-alkyl analogue were determined one hour after injection of the N-alkylated compounds. The drugs administered were the N-2-cyanoethyl-(I) (fenproporex), the N-3-chloropropyl-(II) (mefenorex) and the N-n-propyl-(III) derivatives of AM: the first two of these are used clinically as anorexiants, and the latter has been used extensively to study aspects of metabolism of AM-like compounds. Analysis of AM, I, II and III was performed using electron-capture gas chromatography with a capillary column after reaction of compounds with pentafluorobenzoyl chloride under aqueous conditions. In a second comparative study, equimolar doses (0.05 mMole/kg) of I or AM were administered intraperitoneally to the rats and brain levels determined after one hour. Results indicate extensive N-dealkylation occurs for compounds I, II and III in the rat.
The case of a 12-year-old girl with Gilles de la Tourette's syndrome is presented, and the following factors are discussed: psychological aspects, urinary excretion of 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and unconjugated amines, and CT scan findings. The most noticeable differences from normal controls seen in the urine studies were elevated levels of beta-phenylethylamine and the catecholamine metabolites normetanephrine, MHPG, and 3-methoxytyramine, and a decrease in 5-hydroxytryptamine. A CT scan revealed a slight increase in density in the caudate nuclei bilaterally; this was thought to be due to calcification.
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1. The accumulation of p-chlorophenylethylamine (pCPE) in rat brain after administration of pargyline plus p-chlorophenylalanine (pCPA) is demonstrated. 2. Measurements of pCPE in brain were performed at 0.25 h, 1 h and 4 h after administration of pCPA to pargyline-pretreated rats, and amounts of pCPE were shown to increase with time.
1. Difficulties encountered in the analysis of the monofluorinated amphetamine, 2-amino-3-fluoro-1-phenylpropane (AFP), are discussed. 2. A novel assay procedure and its application to the analysis of AFP in the rat brain are described. The procedure involves pentafluorobenzoylation of AFP under aqueous conditions and quantitation by a gas chromatography equipped with a capillary column and an electron-capture detector.
1. The inhibition of specific 3H-flunitrazepam binding to rat cortical membrane preparations (benzodiazepine receptors) by a series of amide derivatives of beta-carboline and tetrahydro-beta-carboline related to the ethyl ester of beta-carboline 3-carboxylate (beta-CCE) was measured. 2. beta-Carboline amides which are unsaturated in the C ring of the beta-carboline nucleus were the most potent inhibitors of benzodiazepine receptor binding. 3. Increasing the length of the hydrocarbon moiety in the aliphatic amide side chain beyond two carbon atoms decreased potency.
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