Hitoshi Yamaguchi

DM-9384, a new cognition-enhancing agent, increases the turnover of components of the GABAergic system in the rat cerebral cortex

DM-9384 (nefiracetam) (N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide), a pyrrolidone derivative (or a cyclic derivative of gamma-aminobutyric acid (GABA)), is a newly developed nootropic (or cognition-enhancing) agent. In the present study, we examined the biochemical effect of DM-9384 on GABAergic neurons in adult rat brains. DM-9384, when administered orally at a daily dose of 10 mg/kg for 7 days, significantly increased GABA turnover and glutamic acid decarboxylase activity in the cortex and hippocampus, and stimulated Na(+)-dependent high-affinity GABA uptake in cortical synaptosomes. In in vitro experiments, the K(+)-evoked release of [14C]GABA from cortical slices was markedly increased by low concentrations (10(-8), 10(-9) M) of DM-9384. The binding of GABAA and benzodiazepine to their receptors in the brain was not affected by DM-9384 (10(-10)-10(-3) M). The results suggest that DM-9384 increases the turnover of components of the GABAergic system by influencing presynaptic sites rather than postsynaptic sites.

Photoinduced oxygenation of tryptamines by aromatic amine N-oxides

Abstract Irradiation (1) (253-7 nm) of Na,Nb-dimethyltryptaimne with pyridine N-oxide or benzo[c]cinnoline N-oxide in CH2Cl2 yielded 1,8-dimethyl-3a-hydroxy-1,2,3,3a,8-8a,- hexahydropyrrolo[2,3-b]indole (19), while with visible light Nb-(4-cyanobutadienyl)-Na,Nb,- dimethyltryptamine (21) was obtained. This method was applied to trimethyltryptamine and the corresponding oxindole (34) and the N-formyl derivative (20) were obtained.

Synthesis of aromatic and heteroaromatic thioaldehydes, aryl-thioenals, and -thiodienals as their η1; complexes with pentacarbonyltungsten(0) by the reaction of aldimines and a new reagent, [PPh4][W(CO)5SH]

A new reagent, [PPh4][W(CO)5SH]1 for the synthesis of pentacarbonyltungsten(0) complexes of thioaldehydes has been synthesised from [PPh4]SH and [W(CO)5(C4H8O)]. The latter was formed conveniently by a nonphotochemical process. Treatment of each imine 2 with [PPh4][W(CO)5SH]1 in the presence of equimolar mixture of BF3·OEt2 and McCO2H (2 equiv.) gave complexes of the thiobenzaldehydes 3a–j, thionaphthaldehydes 4a–b, thioanthraldehydes 5a–b, 5-methyl-2-thioformylfuran 6, 2-thioformylthiophenes 7a–c, 4-substituted thiocinnamaldehydes 8a–c, and 4-substituted thiocinnamylideneacetaldehydes 9a–c with pentacarbonyltungsten(0) in high yields. NMR studies revealed that the above exist as η1 complexes.

Oxidation of 2,3-disubstituted indoles with m-chloroperbenzoic acid. Formation of o-aminophenol derivatives and a dimeric product

Oxidation of tetrahydrocarbazole (5) with m-chloroperbenzoic acid in methylene dichloride at –60 °C gave the N-benzoyl-o-aminophenol (11) together with the hydroxy-3H-indole (7) and the indol-3(2H)-one (9). The N-benzoyl-o-aminophenol (11) was found to be derived from the hydroxy-4aH-carbazole (7)via an unstable tertiary amine intermediate (17) by further oxidation. The N-benzoyl-o-aminophenol (11) was also obtained by the oxidation of the other hydroxy-3H-indoles (18), (19), and (24). On the other hand, similar oxidation of N-methyl-tetrahydrocarbazole (6) gave the hydroxyenamine (28) and its dimer (27), and of 2,3-diphenylindole (31) and the N-methyl derivative (30) gave the hydroxy-3H-indole (19) and the ketoamide (33), while the 1,4-benzoxazine derivatives (34) and (35) were obtained in the case of the N-acetyl derivative (32).

Oxidation of 2-ethylthioindoles with hydrogen peroxide. Oxidative migration of the ethylsulphonyl group

Oxidation of 2-ethylthioindoles (1) with three molar equivalents of hydrogen peroxide in acetic acid yielded the sulphones (6a, b, and d), the 3-ethylsulphonylindolin-2-ones (7a, b, and d), and the 3-hydroxyindolin-2-ones (8b and d); the sulphoxides (5a, b, d, and e) were the main products with one molar equivalent of hydrogen peroxide. Compounds (7) and (8) were also obtained by oxidation of 2-ethylsulphonylindoles (6) with one molar equivalent of hydrogen peroxide in acetic acid, indicating that oxidative migration of the ethylsulphonyl group was occurring.

Photoinduced oxidation of tryptamine derivatives. Formation of pyrrolo[2,3-b]indole and Nb-(4-cyanobutadienyl)tryptamine

Irradiation (253·7 nm) of NaNb-dimethyltryptamine with pyridine N-oxide produced 1,8-dimethyl-3a-hydroxy-2,3,3a,8a-tetrahydropyrrolo[2,3-b]indole (4), whilst with visible light Nb-(4-cyanobutadienyl)-NaNb-dimethyltryptamine (5) was obtained.