RT Journal Article
SR Electronic
T1 Structure-activity study of the mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. II. Evaluation of the biological activity of the pyridinium metabolites formed from the monoamine oxidase-catalyzed oxidation of MPTP analogs.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 829
OP 835
VO 249
IS 3
A1 S K Youngster
A1 W J Nicklas
A1 R E Heikkila
YR 1989
UL http://jpet.aspetjournals.org/content/249/3/829.abstract
AB In the accompanying paper, several tetrahydropyridine analogs of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were screened for their abilities to be oxidized by monoamine oxidase (MAO) to pyridiniums and to produce neurotoxicity in mice. We reported that most of the analogs were oxidized by MAO to pyridiniums and some of the analogs were neurotoxic. We concluded that the capacity of a tetrahydropyridine MPTP analog to be oxidized by MAO to a pyridinium was a necessary, but not sufficient, condition for the compound to be a neurotoxin. In the present paper we attempt to explain further the neurotoxicity or lack of neurotoxicity of these analogs by evaluating the abilities of the pyridinium compounds to serve as substrates for the neostriatal dopamine (DA) transport system and as inhibitors of mitochondrial respiration. We now report that all of the neurotoxic MPTP analogs are oxidized to pyridiniums that are good substrates for the neostriatal DA carrier and good inhibitors of mitochondrial respiration. The results are consistent with an important role for both uptake of the pyridiniums by the DA carrier and inhibition by the pyridiniums of mitochondrial respiration in the neurotoxicity induced by MPTP and its analogs.