We had previously reported that
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (
MPTP), which produces
Parkinson's disease in humans and animals, inhibited
tyrosine hydroxylation, the rate-limiting step of
dopamine synthesis, in striatal tissue slices after its conversion to
1-methyl-4-phenylpyridinium ion by
monoamine oxidase. In this report, structurally related compounds of
1-methyl-4-phenylpyridinium ion (MPP+) were synthesized and tested for their ability to inhibit
tyrosine hydroxylation in rat striatal tissue slices. The following pyridinium
salts showed inhibitory effect on
tyrosine hydroxylation: pyridinium
salts that substituted the alkyl group for the methyl group of MPP+ (1-ethyl-, 1-propyl-, 1-isopropyl-4-phenylpyridinium
ions); pyridinium
salts that changed the position of the phenyl group (1-methyl-2-phenyl-, 1-methyl-3-phenylpyridinium
ions); pyridinium
salts that modified the phenyl ring at 4 position (1-methyl-4-tolylpyridinium ion, 1-methyl-4-(4'-methoxyphenyl)pyridinium ion); and
N-methylisoquinolinium ion. In contrast, pyridinium
salts in which the phenyl group was replaced with
hydrogen, methyl or methoxycarbonyl group,
paraquat (1,1'-dimethyl-4,4'-dipyridinium
chloride, one of bipyridinium compounds and a widely used
herbicide), and N-methylquinolinium ion, showed no inhibitory effect.
Nomifensine, an inhibitor of
dopamine uptake, prevented the inhibition caused by 1-methyl-2-phenylpyridinium ion. The result suggests that the effective pyridinium
salts are taken up into dopaminergic neurons likewise MPP+ by the
dopamine transport system and inhibit
tyrosine hydroxylation in striatal tissue slices.
N-methylisoquinolinium ion could be one of the candidates of endogenous or environmental factors that produce
Parkinson's disease.