Dianne Shuntich

MPTP To circumvent the laws regarding controlled drugs, a chemist attempted to synthesize a derivative of MEPERIDINE. By synthesizing a new derivative not specifically covered by the CONTROLLED Substances Act and existing Drug Enforcement Agency laws and by synthesizing the drug and selling it within the same state, the chemist had hoped to profit but to avoid violation of the laws. This DESIGNER Drug approach was being widely used to avoid prosecution for selling drugs of abuse—however, in this case a side product was also formed in this reaction, MPTP (1-methyl-4-phenyl-1,2.3,6-tetrahydropyridine). People who bought this mixture on the street quickly developed a neurological syndrome virtually indistinguishable from Parkinson s disease. Initially, the cause of this problem remained unknown. With intense investigation, the blame was placed on the side product in the reaction, MPTP. MPTP had long been used as an intermediate in chemical synthesis and was commercially available. The ability of MPTP to provoke a Parkinson-like syndrome helped explain a report from years ago of a chemist working with this compound suddenly developing a Parkinsonlike disease.

The Parkinson-like syndrome is very similar to the symptoms originally described in Parkinson s disease. The most notable aspects of the syndrome are the marked cog-wheel rigidity of the muscles, along with a generalized decrease in movement usually associated with problems initiating the movement. Patients often have difficulty with fine motor skills, such as writing, and with walking, which usually becomes a series of small, shuffling steps termed a ''festinating gait''; their greatest problem is starting and stopping. Diminished blinking coupled with a limited facial expression can be very prominent and is termed ''masked facies.'' In Parkinson's disease, patients also have a pill-rolling tremor and a tendency to fall, because

MPTP MPDP MPP+

Figure 1

MPTP Conversion to MPDP and MPP+

Figure 1

MPTP Conversion to MPDP and MPP+

of problems with blood pressure and the reflexes important to maintaining posture.

Pathologically, Parkinson's disease is noted for a degeneration of pigmented nuclei within the brain, including the substantia nigra. The loss of the dopaminergic NEURONS in the substantia nigra that project to the part of the brain called the striatum is responsible for the motor problems, while the degeneration of other areas of the brain, including the locus coeruleus, are presumably responsible for the autonomic problems. The cause of Parkinson's disease is still not known; treatment is symptomatic. Early studies demonstrated the ability of anticholinergic medications to help with many of the motor symptoms, especially the tremor. However, the drug of choice in the 1990s is L-dopa, a precursor of DOPAMINE. Unlike dopamine, which does not traverse the blood-brain barrier, L-dopa is readily transported into the brain where it is taken up into neurons and converted to dopamine—thereby helping to reduce symptoms caused by loss of do-pamine-containing neurons. Replacement of the dopamine can markedly limit the severity of the motor symptoms; however, the duration of this benefit is often limited to only about five years, presumably due to the continued progression of the disease.

MPTP does not bind to OPIOID RECEPTORS and it has no opioid activity, although it is a side product in the synthesis of a meperidine analog. When ingested, it is taken up into neurons containing a catecholamine transporter, greatly limiting the neurons affected. Once in the cell, the drug is converted by the enzyme monoamine oxidase (type B) in a series of steps to another compound, MPP +, which is believed to be responsible for its toxic actions. The need for the transporter to take up the toxin into the cells partially explains its selective toxicity within the brain. There, this drug destroys the same groups of pigmented catecholinergic neurons affected in Parkinson's disease, including the substantia nigra and the locus coeruleus. The greater sensitivity of pigmented neurons to the toxin is still not completely understood. One hypothesis has been put forward: The color in the neurons is due to the pigment melanin, which actively binds the toxin. Therefore, it has been suggested that this binding results in the accumulation of very high levels of the drug, which persist in the neurons for long periods of time, enhancing its toxicity.

Clinically, MPTP produces a syndrome virtually identical to that seen in Parkinson's disease, but Parkinson's is a progressive degenerative disease, which, over the period of many years, gradually leads to a variety of difficulties with thought and memory. It is not thought that MPTP produces a similar global, diffuse loss of function. The marked similarity, though, has led to the speculation that Parkinson's may be due to the exposure to a toxin similar to MPTP. Since the toxicity of MPTP depends on its conversion by type B monoamine oxidase (MAO-B), it has been suggested that inhibition of this enzyme may prove beneficial. Seligine is a selective MAO-B inhibitor, and early clinical trials suggest that the progression of Parkinson patients taking this medication may be slower than in the control groups.

BIBLIOGRAPHY

CEDARBAUM, J. M., SCHLEIFER, L. S. (1990). Drugs for Parkinson's disease, spasticity, and acute muscle spasms. In A. G. Gilman et al. (Eds.), Goodman and Gilman's the pharmacological basis of therapeutics, 8th ed. New York: Pergamon.

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