MPPP

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.

This college student was able to successfully make MPPP from meperidine for months for his own use. However, one day while cooking up some MPPP, he was in a hurry and skipped a step or two in the synthesis process. Later, when he decided to inject himself with this latest batch of MPPP, he immediately knew something was wrong when his whole arm began to burn. Within a few days, his arms and legs became completely paralyzed, and he was unable to move or speak. His... 

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... 

The two most common analogs of meperidine used as recreational drugs are l-methyl-4-phenyl-4-propionoxypiperidine (MPPP) and l-[2-phenylethyl]-4-acetyloxypiperdine (PEPAP). These compounds have a number of street names, including new heroin, synthetic heroin, synthetic Demerol, and China White. MPPP and PEPAP have pharmacological effects similar to those of heroin, hut more pronounced, producing a sense of euphoria and release from the real world. MPPP, for example, is three times as potent has heroin. 

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. 

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. 

MPPP is a street drug and not approved by the FDA. If MPPP were to be submitted for regulatory approval, the Parkinson s-related issues of MPPP would likely have been discovered early in animal trials. Regardless, the story of MPPP demonstrates the complexity of anticipating the possible metabolic pathways of drugs. 

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

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.

The effect of N atoms on the mass of the molecular ion in a mass spectrum is called the nitrogen rule A compound that contains an odd number of N atoms gives an odd molecular ion. A compound that contains an even number of N atoms (including zero) gives an even molecular ion. Two street drugs that mimic the effects of heroin illustrate this principle 3-methylfentanyl (two N atoms, even molecular weight) and MPPP (one N atom, odd molecular weight). 

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Arylpiperidines with an Oxygen Substituent at Q Reversal of the ester in meperidine gives MPPP (iV-methyl-4-phenyl-4-... 

A wide variety of modifications have been made to MPPP, including modification of the ester functionality, variation in the nitrogen substituent, substitution on the piperidine ring, etc. (see Ref 405). The propionyl chain is the optimum length, and hydrolysis of the ester to the corresponding alcohol usually results in compounds with little if any activity. Several JV-phenylalkyl substitutions such as phenethyl increase potency in some cases [i.e., the anilino-... 

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.

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