4′-Alkylated analogs of 1-methyl-4-phenylpyridinium ion are potent inhibitors of mitochondrial respiration

Stephen K. Youngster, Martin R. Gluck, Richard E. Heikkila, William J. Nicklas

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)758-764
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume169
Issue number2
DOIs
StatePublished - 15 Jun 1990
Externally publishedYes

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