Norimitsu Hamamichi

Inhibition of rat brain monoamine oxidase by some analogues of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 1-methyl-4-phenylpyridinium ion

To clarify the essential chemical structures of the neurotoxins, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its oxidized product, 1-methyl-4-phenylpyridinium ion (MPP+), that govern nigrostriatal dopamine neuron toxicity, interactions of several structurally related compounds of MPTP or MPP+ with monoamine oxidase (MAO) in rat forebrain homogenates were studied. Of the compounds tested, 4-phenyl-1,2,3,6-tetrahydropyridine (PTP), 4-phenylpyridine and 4-phenylpiperidine strongly and dose-dependently inhibited MAO-A and -B activity. Inhibition of PTP and 4-phenylpiperidine was MAO-A-selective, while that by 4-phenylpyridine was MAO-B-selective. Of these 3 compounds, only PTP time-dependently inhibited MAO-B, but not -A. Without preincubation, the modes of inhibition of MAO-A and -B by PTP were competitive. After 1 h preincubation, the mode of MAO-B inhibition changed to non-competitive, while inhibition of -A remained unchanged. PTP was oxidized by MAO-B, but not by -A, under these conditions. In contrast, 4-phenylpyridine and 4-phenylpiperidine were not substrates for either form of MAO in rat forebrain homogenates. These results, along with the other observations, indicate that PTP may essentially cause a neurotoxic effect on the nigrostriatal dopamine pathway.

Time-dependent inhibition of rat brain monoamine oxidase by an analogue of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP),4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine

Inhibitory effects of some MPTP and MPP+ analogues on rat brain MAO activity were studied to further clarify the structure-activity relationships of MPTP neurotoxicity. Of the analogues tested, 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine (CPTP), 4-(4-chlorobenzyl)-pyridine (CBP), 4-benzylpyridine (BPY) and 4-benzylpiperidine (BPIP) dose-dependently inhibited both MAO-A and -B activities. CPTP, BPY and BPIP showed a higher MAO-A selectivity, while CBP was a selective MAO-B inhibitor. In preincubation studies, only CPTP greatly enhanced the degree of inhibition of MAO-B when the preincubation time was increased, but inhibition of MAO-A was not enhanced. Together with our previous MPTP and MPP+ analogue findings, the present results indicate that, in these chemical structures, a 4-phenyl-1,2,3,6-tetrahydropyridine ring is most essential for time-dependent inhibition of MAO. This chemical requirement is consistent with the ability to cause nigrostriatal dopaminergic neurotoxicity.

Synthesis and mechanism of formation of novel tricyclic nucleosides, 3-β-d-ribofuranosylpyrazolo[3,2-ipurine derivatives, by a one-step reaction of 6-enaminopurine with hydrazine

Abstract Ethyl 3-β-D-ribofuranosylpyrazolo[3,2- i purine-9-carboxylate ( 8 ) has been prepared from a fully protected 6-chloropurine derivative in four steps including a one-step reaction for the preparation of 3-β-D-ribofuranosyl-[3,2- i purine derivative 5 (by 6-enaminopurine and hydrazine, and the mechanism of formation of 5 is discussed.

The Synthesis of 6-C-Substituted Purines via a-(Aminomemthylene)-6-purineacetonitrile

6-Purinemalononitrile, which was prepared by the substitution of 6-chloropurine with malononitrile or deprotection of methoxymethyl group of (9-methoxymethyl-purin-6-yl)-malonitrile with acid, has been catalytically hydrogenated to the α-(aminomethylene)-6-purineacetonitrile (I). Substitution of I with amines gave the corresponding alkylamines. Reaction of I with hydrazine and acetamidine hydrochloride gave pyrazole derivative and pyrimidine derivative, respectively

A convenient method for the synthesis of 6-enaminopurine derivatives by catalytic hydrogenation of 6-cyanomethylenepurines

Abstract 6-Cyanomethylenepurines have been catalytically hydrogenated to the corresponding α-(aminomethylene)purine-6-acetic acid derivatives in good yields using dimethylformamide-benzene as solvent over Pd-C under medium pressure.