Investigation of the possible dopaminergic toxicity of 1-methyl-3-phenyl-1,2,3,6-tetrahydropyridine, an isomer to the neurotoxin MPTP.
1-Methyl-3-phenyl-1,2,3,6-tetrahydropyridine (M-3-PTP) is an analogue to the Parkinson-producing dopaminergic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), M-3-PTP, and simple analogues thereof, are versatile intermediates in organic synthesis. The present study was undertaken to investigate the possible dopaminergic toxicity of M-3-PTP. Male albino mice were injected with 50 mg/kg of either MPTP or M-3-PTP and dopamine (DA) and its metabolites were determined 2 hr and 7 days after the administration. Two hr after MPTP profound acute changes in brain DA metabolism were found, i.e. an approximately 50% reduction in the concentration of DA together with a 10-fold increase in the level of 3-methoxytyramine. Seven days after MPTP, DA and metabolites were markedly reduced which is consistent with a degeneration of the dopaminergic neurones. In contrast M-3-PTP produced no acute or long-term alterations in the concentrations of DA and its metabolites in mouse brain. Furthermore, in vitro experiments show that M-3-PTP does not inhibit monoamine oxidase B. Thus, the present data show that M-3-PTP is devoid of dopaminergic toxicity in mouse brain and is not likely to produce Parkinson's disease in humans. The lack of toxicity is probably explained by the low affinity of M-3-PTP for monoamino oxidase B.
Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Center, Uppsala University, Sweden.
K
K
Nilsson
A
A
Hallberg
E
E
Pileblad
A
A
Tunek
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives*; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D002395:Catecholamines / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology; D004298:Dopamine / Q000031:analogs & derivatives / Q000378:metabolism*; D015259:Dopamine Agents / Q000633:toxicity*; D006719:Homovanillic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D007536:Isomerism; D008032:Limbic System / Q000187:drug effects / Q000378:metabolism; D020267:MPTP Poisoning; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008995:Monoamine Oxidase / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D002395:Catecholamines; D015259:Dopamine Agents; D015102:3,4-Dihydroxyphenylacetic Acid; C048977:1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine; C071719:1-methyl-3-phenyl-1,2,3,6-tetrahydropyridine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase; C001746:3-methoxytyramine; D004298:Dopamine; D006719:Homovanillic Acid