Characterization of the neurotoxic potential of m-methoxy-MPTP and the use of its N-ethyl analogue as a means of avoiding exposure to a possible Parkinsonism-causing agent.

Abstract

1-Methyl-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine (2) produced persistent depletion of striatal dopamine in mice after four daily injections, although it was less potent than 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP has been implicated as a cause of Parkinsonism in drug abusers who inadvertently self-administered it and in industrial chemists who were exposed to it. Our results suggest that the m-methoxy compound has the same neurotoxic potential to cause destruction of nigrostriatal dopamine neurons that would lead to Parkinsonian symptoms in humans. In contrast, 1-ethyl-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine (11) had no effects on striatal dopamine in mice, even at doses 8 times those of MPTP. A method of preparing 11 and using it as an intermediate in the synthesis of potential analgesic drugs, thus avoiding a potentially neurotoxic intermediate, is described.

• Authors: D M Zimmerman, B E Cantrell, J K Reel, S K Hemrick-Luecke, R W Fuller
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 29 Issue 8 Pg. 1517-20 (Aug 1986) ISSN: 0022-2623 [Print] United States
• PMID: 3488406 (Publication Type: Journal Article)

Chemical References

• Pyridines
• 3,4-Dihydroxyphenylacetic Acid
• 1-ethyl-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine
• 1-methyl-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine
• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
• Dopamine
• Homovanillic Acid

Topics

• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
• 3,4-Dihydroxyphenylacetic Acid (metabolism)
• Animals
• Brain (drug effects)
• Corpus Striatum (drug effects, metabolism)
• Dopamine (metabolism)
• Homovanillic Acid (metabolism)
• Mice
• Parkinson Disease, Secondary (chemically induced)
• Pyridines (chemical synthesis, pharmacology, toxicity)
• Structure-Activity Relationship