Hoppel C L, Grinblatt D, Kwok H C, Arora P K, Singh M P, Sayre L M
Department of Pharmacology, Case Western Reserve University, Cleveland, OH.
Biochem Biophys Res Commun. 1987 Oct 29;148(2):684-93. doi: 10.1016/0006-291x(87)90931-4.
In order to clarify the structural requirements associated with the inhibition of mitochondrial respiration by MPP+, the neurotoxic metabolites of the Parkinsonian agent MPTP, ten sets of pyridine/N-methylpyridinium pairs and a few miscellaneous compounds were evaluated on rat liver intact mitochondria (Mw) and on submitochondrial particles (SMP). The pyridinium partners were much more potent inhibitors on Mw than on SMP, indicating that they are concentrated inside mitochondria by the energy-dependent process previously reported for MPP+, probably as a consequence of non-specific passive transport across the mitochondrial inner membrane in response to the transmembrane potential. In the SMP assay, the neutral pyridines were stronger inhibitors than were the pyridinium cations, and the inhibitory potency varied little with structural changes. The N-methylated forms of beta-carbolines may act as endogenous MPP+-like agents.
为了阐明帕金森病药物MPTP的神经毒性代谢产物MPP⁺抑制线粒体呼吸作用所涉及的结构要求，我们对十组吡啶/N-甲基吡啶对以及一些其他化合物在大鼠肝脏完整线粒体（Mw）和亚线粒体颗粒（SMP）上进行了评估。吡啶鎓类化合物对Mw的抑制作用比对SMP更强，这表明它们通过先前报道的MPP⁺的能量依赖性过程在线粒体内浓缩，这可能是由于响应跨膜电位而通过线粒体内膜进行非特异性被动转运的结果。在SMP测定中，中性吡啶比吡啶鎓阳离子是更强的抑制剂，并且抑制效力随结构变化变化不大。β-咔啉的N-甲基化形式可能作为内源性MPP⁺样物质起作用。
