Wieslaw Gessner

Metabolism of the neurotoxin in MPTP by human liver monoamine oxidase B

The neurotoxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) was oxidized to dihydropyridine MPDP+ and pyridine MPP+ by preparations of monoamine oxidase B (MAO B), including pure human liver MAO B:monoclonal antibody complex. K m,app values for MPTP and benzylamine, a preferred MAO B substrate, were 316 and 64 μM, respectively. 4‐Phenyl‐1,2,3,6‐tetrahydropyridine (PTP), the nor derivative of MPTP, was also a substrate (K m,app = 221μM). MPDP+ MPTP, and MPP+, but not PTP, were found tobe irreversible inhibitors of MAO B. Our studies support the hypothesis that MPTP is oxidized in primate brain by MAO B to MPDP+ which is then converted to MPP+ a major metabolite found in the substantia nigra.

Serotonergic conversion of MPTP and dopaminergic accumulation of MPP

[3H]MPP+ had lower K m and higher V max values for its accumulation in rat brain synaptosomes than did [3H]MPTP. The kinetic parameters favored the uptake of [3H]MPP+ in the striatum to that in hypothalamus, whereas they were equally favorable for the uptake of [3H]MPTP in both regions. Hypothalamic uptake of [3H]MPTP and [3H]MPP+ was inhibited by desipramine, imipramine, norepinephrine, and serotonin. Striatal uptake of [3H]MPP+ and [3H]MPTP was blocked by nomifensine and dopamine. These results support the concept that MPTP accumulates in serotonergic neurons where it is oxidized by monoamine oxidase B to MPP+, which is released and then is selectively accumulated in dopaminergic neurons via the dopamine uptake system.

MPTP metabolites inhibit rat brain glutathione S-transferases

1-Methyl-4-phenyl-2,3-dihydropyridinium and 1-methyl-4-phenyl-pyridinium species, metabolites of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, non-competitively inhibit glutathione S-transferases of rat brain in vitro. The Ki values for 1-methyl-4-phenyl-2,3-dihydropyridinium bromide and 1-methyl-4-phenyl-pyridinium bromide are 0.67 and 0.3 mM, respectively. Inhibition of these enzymes may lead to impairment of cellular defense mechanisms.

Photooxidation products of primaquine: structure, antimalarial activity and hemolytic effects

Photooxidation of primaquine (1) and 5‐hydroxyprimaquine (5) afforded a blue dye for which o‐quinone structure 4 was elaborated. Similar oxidation of N‐ethoxyacetylprimaquine (10) afforded o‐quinone 11. Tissue schizontocidal activity of 4 and 11, and bisquinolylmethine 3 prepared earlier, showed that none of them had noteworthy antimalarial activity, but all three produced methemoglobin.

Studies on the mechanism of MPTP oxidation by human liver monoamine oxidase B

The neurotoxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) and its deuterated analogues were oxidized to their corresponding dihydropyridinium species (MPDP+) by preparations of pure human liver MAO B : monoclonal antibody complex to investigate the mechanism of MPTP activation. Lineweaver‐Burk plots of initial reaction rates revealed that the K m,app values for the various deuterated MPTP analogues were similar to those of MPTP. In contrast, V max,app values were substantially decreased by substitution of deuterium for hydrogen on the tetrahydropyridinium ring, especially at C‐6. Deuterium substitution on the N‐methyl group alone did not significantly reduce V max,app. These studies support the interpretation that oxidation of MPTP at the C‐6 position on the tetrahydropyridine ring is a major rate‐determining step in its biotransformation by MAO B.

Reduction of Phenyl-Substituted Pyridinium Methoiodides with Sodium Borohydride. Formation of Amine-Borane Complexes in Water

Abstract Reduction of phenyl-substituted pyridinium methoiodides with sodium borohydride in water afforded besides the desired tetrahydropyridines substantial amounts of amine-borane complexes. Reduction in methanol afforded tetrahydropyridines in high yield, with almost no amine-boranes formed.

Improved Synthesis of the Lukes-ŜOrm Dilactam. Nucleophilic Opening to 5-Substituted 2-Pyrrolidine-2-Ones

Abstract An improved synthesis of the Lukes-Ŝorm dilactam 3 and conversion into several 5-substituted pyrrolidine-2-ones are described.

C(9)-Butylated Lactams Related to Perhydrohistrionicotoxin

Abstract The unsubstituted ketospirolactam 1 afforded on alkyla-tion the two C(9)-butylated ketolactams 2 and 3, with 3 being the more stabile epimer, and the C(9)-dibutylated ketolactam 4. Structure of alcohol 5 obtained from 3 was secured by X-ray analysis.