Inhibition of NADH oxidation by 1-methyl-4-phenylpyridinium analogs as the basis for the prediction of the inhibitory potency of novel compounds

Sergey O. Sablin, Matthew J. Krueger, Victoria L. Yankovskaya, Sergey E. Tkachenko, Alexander N. Razdolsky, Sergey O. Bachurin, Rona R. Ramsay, Thomas P. Singer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

Inhibition of NADH dehydrogenase (Complex I) of the mitochondrial respiratory chain by 1-methyl-4-phenylpyridinium (MPP+) and its analogs results in dopaminergic cell death. In the present study, the inhibition of mitochondrial respiration and of NADH oxidation in inverted inner membrane preparations by the oxidation products of N-methyl-stilbazoles (N-methyl-styrylpyridiniums) are characterized. These nonflexible MPP+ analogs were found to be considerably more potent inhibitors than the corresponding MPP+ derivatives. The IC50 values for these compounds and previously published figures for MPP+ analogs were then used to select a computer model based on structural parameters to predict the inhibitory potency of other compounds that react at the "rotenone site" in Complex I. A series of 12 novel inhibitors different in structure from the basic set were used to test the predictive capacity of the models selected. Despite major structural differences between the novel test compounds and the MPP+ and styrylpyridinium analogs on which the models were based, substantial agreement was found between the predicted and experimentally determined IC50 values. The value of this technique lies in the potential for the prediction of the inhibitory potency of other drugs and toxins which block mitochondrial respiration by interacting at the rotenone sites.

Original languageEnglish
Pages (from-to)33-43
Number of pages11
JournalJournal of Biochemical Toxicology
Volume11
Issue number1
DOIs
Publication statusPublished - 1 Jan 1996

Keywords

  • Complex I Inhibitor
  • Rotenone Sites
  • Structure-Activity Relations
  • Styrylpyridinium Inhibitors

Fingerprint

Dive into the research topics of 'Inhibition of NADH oxidation by 1-methyl-4-phenylpyridinium analogs as the basis for the prediction of the inhibitory potency of novel compounds'. Together they form a unique fingerprint.

Cite this