Structure-activity study of the mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. I. Evaluation of the biological activity of MPTP analogs.
Several analogs of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were synthesized and compared to MPTP for their ability to be oxidized by monoamine oxidase (MAO) and for their ability to cause nigrostriatal dopaminergic neurotoxicity in mice. Most of the compounds were oxidized by mouse brain MAO, either predominantly by the B-form or by both the A- and B-forms. The MAO-catalyzed oxidation of all of the MAO substrates resulted in the formation of dihydropyridinium intermediates which, in turn, except for the dihydropyridinium of 1-methyl-4-benzyl-1,2,3,6-tetrahydropyridine, formed pyridinium species as the final oxidation product. Nine analogs were found to be neurotoxic; all were oxidized by MAO to pyridinium compounds. However, some non-neurotoxic MPTP analogs were also oxidized by MAO. Neither 1-methyl-4-benzyl-1,2,3,6-tetrahydropyridine nor the compounds which were not substrates for MAO were neurotoxic. Also, the neurotoxicity of all of the compounds tested was blocked by inhibiting either MAO-B, MAO-A or both MAO-B and MAO-A together, indicating that MAO activity was necessary for the neurotoxicity of the compounds to be manifested. The capacity of an MPTP analog to be oxidized by MAO to a pyridinium appears to be a necessary, but not sufficient, parameter in determining the neurotoxic potential of the compound.
Youngster
S K
SK
Department of Neurology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway.
Sonsalla
P K
PK
Sieber
B A
BA
Heikkila
R E
RE
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004347:Drug Interactions; D008297:Male; D051379:Mice; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D010084:Oxidation-Reduction; D011725:Pyridines / Q000378:metabolism / Q000633:toxicity*; D013329:Structure-Activity Relationship
D008996:Monoamine Oxidase Inhibitors; D011725:Pyridines; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase; D004298:Dopamine