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.
Sablin
S O
SO
Molecular Biology Division, Veterans Affairs Medical Center, San Francisco, CA 94121, USA.
Krueger
M J
MJ
Yankovskaya
V L
VL
Tkachenko
S E
SE
Razdolsky
A N
AN
Bachurin
S O
SO
Ramsay
R R
RR
Singer
T P
TP
D015655:1-Methyl-4-phenylpyridinium / Q000031:analogs & derivatives* / Q000633:toxicity*; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects; D015259:Dopamine Agents / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006540:Herbicides / Q000633:toxicity*; D007928:Lethal Dose 50; D008930:Mitochondria, Liver / Q000187:drug effects; D009245:NADH Dehydrogenase / Q000037:antagonists & inhibitors*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D011726:Pyridinium Compounds / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D013329:Structure-Activity Relationship
D015259:Dopamine Agents; D006540:Herbicides; D011726:Pyridinium Compounds; D009245:NADH Dehydrogenase; D015655:1-Methyl-4-phenylpyridinium