W. Th. Nauta

THE EFFECT OF PSYCHOTROPIC DRUGS ON γ‐AMINOBUTYRIC ACID AND GLUTAMIC ACID IN BRAIN TISSUE

SOME time ago, one of us (DE WAART, 1956, 1958) published the results of an investigation of the inhibitory effect of a number of diphenhydraminef derivatives on intermediary metabolism. Like the barbiturates, diphenhydramine reduces the oxygen consumption during the aerobic metabolism of rat brain slices (glucose as substrate). The compounds studied at the time mainly consisted of alkyl derivatives of diphenhydramine. Generally speaking, these derivatives display a more pronounced inhibitory effect than diphenhydramine itself. It was also found that some compounds examined affected the amino acid metabolism. By paper chromatography it was demonstrated that at the end of the experiments the concentration in the incubation fluid of some of the amino acids which are released initially (McLwm, 1959) remained at a high level, whereas in the blanks these acids were regained by the tissue. After ninhydrin coloration the chomatograms showed four bands, two of which were particularly distinct. These were identified at the time as glutamic acid and methionine. Barbiturates did not have this effect on the amino acid pattern of the incubation fluid. Of the compounds investigated, orphenadrine (,!I-dimethylaminoethyl-2-methylbenzhydrylether, Disipal @) produced the strongest effect. The pharmacological properties of orphenadrine are very different from those of diphenhydramine. (It has a strongly reduced antihistamine action and a strongly increased atropine one.) The preparation is used for treating Parkinsonism, and recent investigations (SCHEURLE, 1957; ROBITSCHER, 1958; PFEIFFER, 1959) show that it also has psychotropic prop-ties. These observations prompted us to study the effect of psychotropic drugs on amino acid metabolism also. A preliminary note on the results of this investigation was published by us some time ago (NAUTA et al., 1958).

Investigations into the metabolic fate and distribution of hepzidine maleate in the rat and the mouse

Abstract Metabolic studies with hepzidine maleate, labelled in two positions with 3H and 14C, respectively, showed that in rats, over 50 per cent of an orally administered dose of hepzidine maleate (10 mg kg ) is hydrolysed before absorption. The nonhydrolysed part of the dose is absorbed to a large extent. An important biotransformation of hepzidine is N-demethylation; it involves about 20 per cent of a 10- mg kg oral dose and over 37 per cent of an equal dose, given i.p. On the other hand, N-demethylation of the hydrolytic product 1-methyl-4-piperidinol was very slight. Excretion of 14C radioactivity in the expired air shows good first-order kinetics, from which a half-life of about 4.2 hr could be evaluated for hepzidine maleate in the rat. Next to urinary excretion, biliary excretion plays an important role in the elimination of hepzidine maleate and metabolites. In the urine the hydrolytic products of hepzidine, especially 1-methyl-4-piperidinol and its metabolites (probably conjugates) are predominant. There is evidence that in bile the hydrolytic product 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ol and its metabolites (probably conjugates) are predominant, but in contrast to urine a substantial amount of the hepzidine is excreted in bile as such and/or in some form which still possesses the intact hepzidine structure. After i.p. administration of hepzidine maleate-14C to female mice (50 mg kg ) autoradiographic distribution studies show the radioactivity to attain considerable levels in most organs, while blood levels stay relatively low. Highest accumulations of radioactivity are found in the liver, lungs, hypophysis, Harders gland, submaxillary gland, mucous glands in tongue, palatum and pharynx, bone marrow, lymphoid tissue, urinary bladder wall, urine, bile, intestinal contents, and specified zones in the kidneys and adrenals. To a lesser degree there is also a pronounced penetration of radioactivity into the CNS, where hippocampus, cerebral cortex and thalamus show a higher degree of radioactivity than other brain areas. In most organs maximum levels are observed at 1 hr after administration. No specific long-lasting accumulations of radioactivity have been observed, except in the urinary bladder wall, which still shows a high level of radioactivity at 16 hr after administration.

In vitro precipitation of liver microsomes by deptropine and some structurally related compounds: A cause for the discrepancies observed between in vivo and in vitron-demethylation

Abstract Deptropine, 3α-(9,10-dihydro-5 H -dibenzo[a,d]cyclohepten-5-yloxy) tropane, and some structurally related compounds were found to associate with and to precipitate rat liver microsomes in vitro . This provides an explanation for the following findings: in vitro deptropine is poorly demethylated; it inhibits the demethylation of other substrates; concentrations upwards of about 3.10 −4 M exert an inhibitory effect on the NADPH-oxidase in suspensions of rat liver microsomes. However, the drug is well demethylated in intact rats: within 6 hr after intraperitoneal administration more than 22 per cent is metabolised by this route.

Pharmacokinetics of 2-phenyl-1,3-indandione in the rat after i.v. and oral administration.

SummaryThe pharmacokinetics of the anticoagulant drug, 2-phenyl-1,3-indandione, after i.v. and oral administration in the rat might be best described as a non-linear open two-compartment model with elimination from the peripheral compartment. The volume of the central compartment comprises the extracellular fluid.

Investigation into the tuberculostatic activity of some derivatives of p. aminobenzoic acid

SummarySeventy-five compounds, derivatives of 4-nitro-benzoic acid and of 4-amino-benzoic acid, were investigated for their tuberculostatic activity. The majority showed practically no activity in the concentrations studied. A number of 4-nitro-benzoic acid esters of branched alcohols, which proved to be active on the synthetic medium, showed a considerably lower activity on the protein-containing Beeuwkes medium.The synthesis of the esters mentioned, and that of n-hexylamino-benzoic acid, 4-acetylamino-3-amino-benzoic acid, and 5,5′-dinitro-2,2′-dicarboxy-diphenyl is described. The melting point of 4-thio-ureido-benzoic acid was higher than 330°C. in our investigation, and was not at 255°C. as mentioned in the literature.

Effects of 2-aryl-1,3-indandiones on the reduction of 2,6-dichlorophenol indophenol by methemoglobin reductase.

Abstract Both steric and electronic factors appeared to be essential to the interaction of 2-aryl-1,3-indandiones with methemoglobin reductase. 2-Phenyl-1,3-indandione, 2-(3,5-di- tert .butylphenyl)-1,3-indandione and 2-(4-methoxyphenyl)-1,3-indandione were found to be cofactors of the enzyme. By introducing electron-attracting substituents into the phenyl ring strong competitive inhibitors were obtained: 2-(3,5-dichlorophenyl)-1,3-indandione and 2-(3,5-di-trifluoromethylphenyl)-1,3-indandione. Two ortho-substituted derivatives, 2-(2,6-dimethylphenyl)-1,3-indandione and 2-(2,4,6-trimethylphenyl)-1,3-indandione, had no effect at all on the reduction. The anti-inflammatory activities of 2-aryl-1,3-indandiones, as determined in a carrageenan oedema test, showed no relationship to the interaction with the enzyme.