Cytotoxic catecholamine analogs

Cytotoxic catecholamine analogs

Like DOPA and methyldopa, 6-hydroxydopa (Figure 10.20a) finds its way into catecholaminergic nerve ter-minals; it is decarboxylated inside the cell to 6-hydroxy-dopamine. The latter compound, however, does not act as a false transmitter. Instead, it acts as an inhibitor of the mito-chondrial respiratory chain, apparently by binding to com plex I (NADH dehydrogenase). This leads to degeneration of the norepinephrine- or dopaminergic neurons. When applied to newborn rats, it largely destroys the sympathetic nervous system (both its central and peripheral parts), and it is being used for this purpose in experimental research.

A drug with a similar mode of action is Methyl-phenyl-tetrahydropyridine (MPTP; Figure 10.20b). This substance is is converted (apparently by monoamine oxidase, which also oxidizes the regular catecholamine transmitters) to 1-Methyl-4-phenyl-pyridinium (MPP). MPP is again an inhibitor of mitochondrial NADH dehydrogenase. Since MPTP enters the neurons through the dopamine reuptake transporter, it acts selectively on dopaminergic cells and, accordingly, gives rise to a drug-induced form of Parkin-son's disease. Of course, MPTP is not being used in clin-ical medicine. It is formed as a by-product in the synthe-sis of 1-methyl-4-phenyl-4-propionoxy-piperidine (MPPP, Figure 10.20b), which in turn has a morphine-like mode of action. The poisonous action of MPTP was discovered ac-cidentally when drug addicts suddenly developed the symp-toms of Morbus Parkinson after partaking of a batch of MPPP from an illegally (and, it would seem, unprofession-ally) operated laboratory that contained an exceptionally high proportion of MPTP. MPTP has, however, subsequent-ly found application in experimental research on the latter disease with animals.