MPPP, MPTP

Of the two analogs, MPPP poses a somewhat more serious threat to users because a highly toxic by-product, l-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), is sometimes formed during its synthesis. MPTP forms during the synthesis of MPPP if the pH of the reaction solution is too low or the reaction temperature is too high. Thus, errors that might appear relatively minor to an inexperienced chemist can result in a contaminated product (MPPP + MPTP) that is highly toxic to users. 

Fig. 11.14 Structures of the phenylpiperidine, meperidine reverse meperidine (MPPP), MPTP, and MPP+.

Recently much interest has centred on a very specific toxin for DA neurons. This is 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP). It was discovered when a student, who was addicted to pethidine, tried to manufacture l-methyl-4-phenyl-4-propionoxy-piperidine (MPPP) but took a short-cut in synthesis and produced MPTP. When he administered this to himself he developed Parkinsonism. MPTP destroys DA neurons. Again this process depends on the neuronal uptake mechanism, since MPTP itself is not the active material. It needs to be deaminated to MPP+ which is then taken up by DA nerve terminals. 

Figure 7.4 The chemical structure of meperidine, its analogue MPPP, and the closely related neurotoxin MPTP, are all shown here. Meperidine, an anesthetic, was also used as an alternative to morphine. It proved advantageous because it has a shorter length of duration and fewer side effects than morphine.

Unaware of it at the time, the college student s sloppy chemistry had, in addition to synthesizing MPPP, inadvertently created some additional by-products that were very toxic. It turns out that one of the by-products, called l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is very toxic to neurons in... 

However, MPPP is sometimes contaminated with the side reaction product l-methyl,4-phenyl-l,2,3,6-tetra-hydropyridine (MPTP), which produces a parkinsonian syndrome through nigrostriatal lesions. Several substituted derivatives of amphetamine have also been called designer drugs. The most widely known of this group is the hallucinogen MDMA (ecstasy). 

In the early 1980s, a form of designer meperidine, known as MPPP, was being illegally manufactured. MPPP was also referred to as synthetic heroin. In some cases, the chemical technique was not precise, and a toxic chemical byproduct, MPTP, was produced. MPTP is a known industrial toxin that can destroy nerve cells in certain portions of the brain... 

The drug in question was l-methyl-4-phenyl-4-propionoxypiperidine (MPPP, 8.85) (Scheme 8.23). During its synthesis, if MPPP is exposed to acid at elevated temperatures, an elimination occurs to afford 1-methyl-4-phenyl-l,2,5,6-tetrahydropyridine (MPTP, 8.86) as an impurity. MPTP is the key impurity responsible for Parkinson s symptoms. 

Figure 10.20. Stractures of cytotoxic catecholamine analogues, a 6-Hydroxdopa is converted to the cytotoxic metabolite 6-hy-droxydoapamine. b Methyli)henyl-tetrahydropyridine(MPTP) is formed as a byproduct of the synthetic opioid 1-methyl-l-phei rM-propionoxy-piperidine (MPPP). It is converted to the cytotoxic metabolite methyl hei rl-pyridinium, probably by monamine oxidase.

Figure 12.3. Phenylpiperidine analgesics and metabolic activation of MPTP. In efforts to synthesize the meperidine-like analgesic agent MPPP ("designer heroin,") (4), MPTP (3)can be formed. It is converted selectively by monoamine oxidase type B (MAO-B, inhibited by agents including deprenyl (selegiline)and pargylineto MPDP (7), and thence to MPP" (8)the proposed toxic species that accumulated in dopamine neurons to result in disruption of their cellular respiration and death.

In the late 1970s a substantial clue to the cause of the nerve cell destruction in Parkinson s disease was provided by young drug addicts using the synthetic heroin substitute MPPP (l-methyl-4-phenyl-4-proprionoxypiperidine) (Figure 14B). Several unfortunate individuals, later found to have consumed MPPP, were diagnosed with Parkinson s disease despite their youth and lack of a family history of the disease. Considerable research revealed that under certain reaction conditions the synthesis of MPPP produces a toxic by-product called MPTP (l-methyl-4-phenyl-l,2,3,6-tetrahy-dropyridine). Once it has been consumed, MPTP is converted to MPP+ (l-methyl-4-phenylpyridinium) in the brain by the enzyme monoamine oxidase. After its synthesis, MPP+ is transported by a... 

MPPP, also referred to as meperidine, is a synthetic analgesic with morphinelike properties. If the chemical reaction used to synthesize MPPP is not carefully regulated, a toxic by-product is also produced. When this latter molecule, MPTP, is inadvertently consumed, it is converted in the brain to MPP+, a neurotoxic agent, in an oxidation reaction catalyzed by monoamine oxidase (see p. 517). 

Fig. 25.5. Chemical conversion of MPPP and probable mechanism of MPTP neurotoxicity.

FIGURE 16.8 MPTP and MPPP were discovered in a mixture that induced PD-like symptoms. MPP is a toxic product of MPTP metabolism. 

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