4'-alkylated analogs of 1-methyl-4-phenylpyridinium ion are potent inhibitors of mitochondrial respiration.
1-Methyl-4-phenylpyridinium ion, a major brain metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, is an inhibitor of Complex I of the mitochondrial respiratory chain. We have synthesized several analogs of 1-methyl-4-phenylpyridinium ion containing various alkyl groups in the 4' position of the phenyl ring and have tested them for their abilities to inhibit the oxidation of NADH-linked substrates by intact mouse liver mitochondria. These compounds are considerably more potent inhibitors than MPP+ itself, with potency increasing as the length of the alkyl chain increases. The most potent inhibitor, 1-methyl-4-(4'heptylphenyl)pyridinium ion, was about 200 times as effective as MPP+. These analogs should prove to be useful tools for studying the nature of the process whereby MPP+ and its pyridinium analogs interact with Complex I to inhibit mitochondrial respiration.
Youngster
S K
SK
Department of Neurology, UMDNJ-Robert Wood Johnson Medical School, Piscataway 08854.
Gluck
M R
MR
Heikkila
R E
RE
Nicklas
W J
WJ
D015655:1-Methyl-4-phenylpyridinium / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D005971:Glutamates / Q000378:metabolism; D007700:Kinetics; D008293:Malates / Q000378:metabolism; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D015394:Molecular Structure; D010101:Oxygen Consumption / Q000187:drug effects*; D013329:Structure-Activity Relationship
D005971:Glutamates; D008293:Malates; D015655:1-Methyl-4-phenylpyridinium