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

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. © 1996 John Wiley & Sons, Inc.