1 -Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Barcia C., Bautista V., Sanchez-Bahillo A. el al (2003). Circadian determinations of cortisol, prolactin and melatonin in chronic methyl-phenyl-tetrahydropyridine-treated monkeys. Neuroendocrinology 78, 118-28. 

Another synthetic heroin-like compound was sold to heroin-dependent individuals in California in 1982 as "new heroin", which was soon recognized to cause severe Parkinsonian symptoms in young people. Eventually it was discovered that "new heroin" contained pethidine together with an N-methyl-phenyl-tetrahydropyridine (MPTP) contaminant. It is now established that MPTP is converted to a neurotoxic... 

Blanchet PJ, Konitsiotis S, Whittemore ER et al (1999) Differing effects of N-methyl-D-aspartate receptor subtype selective antagonists on dyskinesias in levodopa-treated l-methyl-4-phenyl-tetrahydropyridine monkeys. J Pharmacol Exp Ther 290 1034-1040... 

Methyl 1 -phenyl-4-(phenylammo)-2,6-bis(3-(trifluoro methyl)phenyl)-l,2,5,6-tetrahydropyridine-3-carboxylate (4a) Pale yellow solid, mp 140-142 °C reaction time 45 h yield 80%... 

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. 

Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-indueed parkinsonian syndrome in Macaca fascicularis Which midbrain dopaminergic neurons are lost Neuroscience 24 161-174, 1988. 

Bums, R.S. Chieuh, C.C. Markey, S.P. Ebert, M.H. Jacobowitz, D.M. and Kopin, I.J. A primate model of parkinsonism Selective destraction of dopaminergic neurons in the pars compacta of the substantia nigra by n-methyl-4-phenyl-l,2,3,6-tetrahydropyridine.. Proc Natl Acad Sci USA 80 4546-4550, 1983. 

The neurotoxic effects of all these compounds are antagonized by inhibitors of monoamine uptake (table 1), implicating the membrane uptake carrier on serotonin and dopamine neurons in the mechanism of neurotoxicity. In this regard, these amphetamines are like a drug somewhat related in structure, namely l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP), a Parkinsonism-causing neurotoxic dmg that has been studied intensely since 1983 (Langston and Irwin 1986). In the case of MPTP, the mechanism by which inhibitors of the dopamine uptake carrier block the neurotoxicity toward dopamine neurons (mainly nigrostriatal dopamine neurons) seems clear. A metabolite of MPTP, l-methyl-4-phenylpyridinium (MPP-I-), has been shown to be a substrate for the dopamine uptake carrier (Javitch et al. 1985). Thus accumulation of MPP-I-, formed metabolically from... 

Cohen, G., and Mytilineou. C. Studies on the mechanism of action of l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP). Life Sci 35 237-242, 1985. 

Ali, S.F., Martin, J.L., Black, M.D., Itzhak, Y. Neuroprotective role of melatonin in methamphetamine-and l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine-induced dopaminergic neurotoxicity. Ann. N.Y. Acad. Sci. 890 119, 1999. 

Phenyl-l,2,3,6-tetrahydropyrido[2,l- ][l,3]thiazino[3,2- ]quinolin-6-ones were prepared by the reaction of 2-mercapto-5-phenyl-l,4-dihydroquinolin-4-ones with 1,3-dihalopropane <1997JAK97/278780>. 7-Acetyl-2-aryl-9-cyano-6-methyl-8-phenyl-3,4-dihydro-277,877-pyrido[2,l- ][l,3]thiazin-4-ones were obtained from 5-acetyl-3-cyano-6-methyl-4-phenyl-l,2,3,4-tetrahydropyridine-2-thione with 3-aryl-2-propenoyl chloride <2002CHE761>. Reaction... 

Dihydroxybenzoic acid (DHB) is also a commonly used tool to measure the pharmacological effects of HIF-la stabilization via PHD inhibition. Recently, it was shown that mice pretreated with DHB (100 mg/kg, i.p.) showed a marked resistance to the neurotoxic effects of l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) via protection of dopaminergic cell loss and striatal denervation. Importantly, this protection was seen to coincide with HIF-la stabilization, and the prevention of the MPTP-induced loss of ferroportin and striatal iron. Additionally, in these studies, DHB was also observed to block MPTP-induced reduction in mitochondrial pyruvate dehydrogenase, at both the mRNA level and through the measurement of enzyme activity in midbrain substantia nigra [26]. 

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