Studies on the Characterization of the Inhibitory Mechanism of 4′‐Alkylated 1‐Methyl‐4‐Phenylpyridinium and Phenylpyridine Analogues in Mitochondria and Electron Transport Particles

Abstract

1-Methyl-4-phenylpyridinium (MPP+), the toxic agent in MPTP-induced dopaminergic neurotoxicity, is thought to act by inhibiting mitochondrial electron transport at complex I. This study examined this latter action further with a series of 4'-alkylated analogues of MPP+. These derivatives had IC50 values that ranged from 0.5 to 110 microM and from 1.6 to 3,300 microM in mitochondria and electron transport particles (ETPs), respectively. The IC50 values of corresponding 4'-alkylated phenylpyridine derivatives to inhibit NADH-linked oxidation ranged from 10 to 205 microM in mitochondria and from 1.7 to 142 microM in ETPs. The potencies of both classes of inhibitors directly correlated with their ability to partition between 1-octanol and water. In mitochondria, increased hydrophobicity resulted in greater inhibition of NADH dehydrogenase but a smaller dependence on the transmembrane electrochemical gradient for accumulation of the pyridiniums as evidenced by an approximately 600-fold, versus only a 36-fold, increase in the IC50 of MPP+ versus 4'-pentyl-MPP+, respectively, in the presence of uncoupler. In ETPs, the analogous increase in potencies of the more hydrophobic analogues was also consistent with an inhibitory mechanism that relied on differential partitioning into the lipid environment surrounding NADH dehydrogenase. However, the pyridinium charge must play a major role in explaining the inhibitory mechanism of the pyridiniums because their potencies are much greater than would be predicted based solely on hydrophobicity. For example, in ETPs, 4'-decyl-MPP+ was nearly 80-fold more potent than phenylpyridine although the latter compound partitions twice as much into 1-octanol.(ABSTRACT TRUNCATED AT 250 WORDS)