The mutagenic activity of twenty-nine new N-acylglycinohydroxamic acids and related compounds was tested on Bacillus subtilis (Rec⁺, Rec^-) and Salmonella typhimurium (TA 98, TA 100). All the N-(substituted-benzoyl) glycinohydroxamic acids, except 3-acetylaminobenzoyl-derivative, were shown to be mutagenic to both test bacteria, whereas most of the N-aliphatic acylglycinohydroxamic acids were found to be non-mutagenic. In the present study, we discussed our observations focussing on the structure-activity correlation between their chemical structures and mutagenic activities.

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New electronic substituent parameters for quantitative drug design were developed from the standpoint of the frontier orbital theory using the extended Huckel method. Each substituent was characterized by three constants (E, Re, I), which were derived from the SOMO (solely occupied molecular orbital) energy and the coefficient of the SOMO hybrid orbital responsible for bonding to the parent moiety. These correspond to the SOMO-SOMO energy difference (E), the resistivity of the path (Re), and the flow intensity (I) respectively, when the frontier electron flow occurs between the standard parent and the substituent. They can be regarded as major factors governing the electronic inductive-field effect of the substituent. As the result of analyses of various kinds of biological data, they were found to be excellent and widely applicable parameters to the structure-activity problems. In this paper, the new frontier substituent constant values for 150 kinds of substituents and 58 kinds of equations to which the new constants were successfully applied are presented.

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In order to elucidate the biochemical basis for the selective cytotoxicity of D-glucosamine to neoplastic cells, the effect of glucosamine on the growth and several functions of mastocytoma P-815 cells were examined. Incubation of mastocytoma cells with 5 mM glucosamine resulted in a marked inhibition of growth and a significant reduction of cellular uptake and oxidation of glucose and of cellular levels of adenosine triphosphatase (ATP). Glucosamine also reduced the uridine nucleotide pool sizes, and accumulated uridine diphosphate (UDP)-N-acetylglucosamine. However, growth inhibition by glucosamine, which was reversed by glucose, was not prevented by exogenous uridine. In addition, glucosamine suppressed the phosphorylation of thymidine and its incorporation into deoxyribonucleic acid (DNA). The suppression of cell division by glucosamine was accompanied by the elevation of several functions of mastocytoma cells, including the accumulation of adenosine-3', 5'-monophosphate (cAMP), histamine, and serotonin. The incorporation of [³⁵S] SO₄^2-into acidic glycosaminoglycan was also increased. Of these functional alterations, the elevation of cAMP levels was the earliest detectable change, indicating that growth and functions of mastocytoma cells are also regulated by cAMP. However, glucosamine did not affect the adenylate cyclase activity of plasma membrane in vitro. suggesting the necessity of intact membrane structure for the action of glucosamine.

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Several N-substituted-3-acyl-2, 5-dimethyl pyrrole derivatives were examined for their potency to inhibit aggregation of platelets in vitro and extra vivo in guinea pigs. A structure-activity relationship study showed that the substitution at 3 position of the pyrrole ring affected in vitro activity of inhibiting platelet aggregation. Compounds with 3-benzoyl or 3-thenoyl substituent had greater potency than those with 3-aliphatic acyl substituent. Modification of benzoyl, such as para substitution of phenyl group or reduction of carbonyl group, decreased the activity. There was no clear correlation between that N-substitution of the pyrrole ring and in vitro anti-platelet activity. However, compounds with a longer alkyl chain in the N-substituent had weaker activity. The in vitro inhibitory activity on prostaglandin synthetase of these compounds, though less potent compared with their antiplatelet activity, has a close correlation with the latter. N-substituents of the pyrrole ring had the effect on extra vivo activity. Compounds which have no N-α-methyl group and no hetero atoms such as oxygen or sulfur in the N-substituent diminished the extra vivo activity.

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The mean hepatic extraction ratio (ER^^-) of propranolol was estimated directly by simultaneous measurements of arterial and hepatic venous blood concentrations of the drug following systemic venous and portal venous administration in the rat. The ER^^- was greater than 0.9 in the dose range of 2.5 to 12.5 mg/kg following rapid infusion of propranolol into the femoral vein and was not dependent on infusion rate. On the other hand, the ER^^- following intraportal constant-rate infusion decreased progressively with increasing dose, although the ER^^- at an intraportal dose of 2.5 mg/kg was as high as that found after administration into the femoral vein. In addition, it was found that the ER^^- at an intraportal dose of 12.5 mg/kg of propranolol was significantly influenced by infusion rate. The unusual AUC-dose relationship of propranolol previously reported in the rat could be explained on the basis of the present nonlinear hepatic extraction depending on the route and rate of administration which was clarified in vivo. The nonlinear hepatic extraction was further confirmed by determining the remarkably decreased ER^^- of ¹⁴C-propranolol given intravenously after pretreatment or during portal venous administration of unlabelled propranolol.

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The effect of chlorpromazine on phospholipid metabolism was studied in rat liver endoplasmic reticulum. Administration of chlorpromazine per os caused a marked increase in microsomal phospholipid content without affecting its composition. The rate of incorporation of both [³²P] orthophosphate and [2-³H] glycerol into phosphatidic acid and phosphatidylinositol increased by the administration of chlorpromazine. Enhanced labeling of phosphatidylinositol was also observed when myo-[2-³H] inositol was used as a precursor. The activity of glycerophosphate acyltransferase significantly increased and that of phosphatidate phosphohydrolase markedly decreased by the administration of chlorpromazine. The activity of phosphatidate cytidylyltransferase was not affected by the drug treatment. These findings suggested that the administration of chlorpromazine increases the avaliability of phosphatidic acid by activating glycerophosphate acyltransferase and inhibiting phosphatidate phosphohydrolase, leading to enhanced synthesis of phosphatidylinositol.

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After the administration of iproniazid to rabbits and rats, a harmful metabolite, hydrazine, was detected in urine and plasma by means of gas chromatography and gas chromatography-mass spectrometry. The amount of excreted hydrazine from iproniazid was much more than that from isoniazid.

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Effects of a dodecapeptide containing the γ-MSH sequence on two types of conditioned behaviors were investigated. This peptide enhanced the avoidance response in poorlyperforming mice, while it suppressed the self-stimulation lever pressing in rats. At higher doses, the peptide induced slight convulsions of a myoclonic type. The significance of these behavioral changes has not been assessed, but the results suggest that γ-MSH may have some physiological function in the central nervous system.

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