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NEUROPHARMACOLOGY

Block of Delayed-Rectifier Potassium Channels by Reduced Haloperidol and Related Compounds in Mouse Cortical Neurons

European Neuroscience Institute, Göttingen, Germany (S.-B.Y., M.R.); and Institut für Organische und Biomolekulare Chemie, Georg-August-Universität, Göttingen, Germany (F.M., L.F.T.)

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 µM, 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.

Address correspondence to: Shi-Bing Yang, Waldweg 33, 37073 Göttingen, Germany. E-mail: syang1{at}gwdg.de

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