Yang Shi-Bing, Major Felix, Tietze Lutz F, Rupnik Marjan
European Neuroscience Institute, Göttingen, Germany.
J Pharmacol Exp Ther. 2005 Oct;315(1):352-62. doi: 10.1124/jpet.105.086561. Epub 2005 Jul 12.
Haloperidol is known as an antagonist of dopamine D2 receptors. However, it also blocks a variety of ion channels at concentrations above the therapeutic range. Reduced haloperidol (R-haloperidol), one of the main metabolites of haloperidol, has been reported to accumulate in certain tissues, particularly in brain cortex, and it may produce the pharmacological effects associated with haloperidol treatment. In this study, we assessed the effect of R-haloperidol and other related compounds on native delayed-rectifier potassium channels (K(DR)) in mouse cortical neurons by using the whole-cell patch-clamp technique. Although R-haloperidol has much lower affinity to D2 receptors than haloperidol, the IC50 of R-haloperidol to block K(DR) currents was 4.4 microM, similar to its parent compound. The binding site of R-haloperidol is on the cytoplasmic side of the channel because its quaternary derivative preferentially inhibited the currents from intracellular side. 4-Chlorophenyl-4-hydroxypiperidine (4C4HP) is the active fragment of haloperidol because other compounds containing this moiety, including L-741,626 (3-[4-(4-chlorophenyl)-4-hydroxypiperidin-L-yl]-methyl-1H-indole) and loperamide, also blocked K(DR) channels. The potency of the 4C4HP fragment positively correlated with the hydrophobicity index (clogP) of the compounds tested. We conclude that R-haloperidol is a K(DR) channel blocker, although it does not interfere with the normal channel function at a clinically relevant concentration.
氟哌啶醇是一种已知的多巴胺D2受体拮抗剂。然而，在高于治疗范围的浓度下，它也会阻断多种离子通道。还原氟哌啶醇（R-氟哌啶醇）是氟哌啶醇的主要代谢产物之一，据报道它会在某些组织中蓄积，尤其是在大脑皮层，并且可能产生与氟哌啶醇治疗相关的药理作用。在本研究中，我们使用全细胞膜片钳技术评估了R-氟哌啶醇和其他相关化合物对小鼠皮层神经元中天然延迟整流钾通道（K(DR)）的影响。尽管R-氟哌啶醇对D2受体的亲和力远低于氟哌啶醇，但其阻断K(DR)电流的IC50为4.4微摩尔，与其母体化合物相似。R-氟哌啶醇的结合位点在通道的胞质侧，因为其季铵衍生物优先从细胞内侧抑制电流。4-氯苯基-4-羟基哌啶（4C4HP）是氟哌啶醇的活性片段，因为其他含有该部分的化合物，包括L-741,626（3-[4-(4-氯苯基)-4-羟基哌啶-L-基]-甲基-1H-吲哚）和洛哌丁胺，也能阻断K(DR)通道。4C4HP片段的效力与所测试化合物的疏水指数（clogP）呈正相关。我们得出结论，R-氟哌啶醇是一种K(DR)通道阻滞剂，尽管它在临床相关浓度下不会干扰正常通道功能。
