JPET

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on July 12, 2005; DOI: 10.1124/jpet.105.086561

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jpet.105.086561v1
315/1/352    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yang, S.-B.
Right arrow Articles by Rupnik, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yang, S.-B.
Right arrow Articles by Rupnik, M.


Received for publication March 18, 2005.
Revised July 7, 2005.
Accepted for publication July 7, 2005.

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

Shi-Bing Yang 1*, Felix Major 2, Lutz F Tietze 2, Marjan Rupnik 1

1 European Neuroscience Institute Goettingen 2 Institut fur Organische und Biomolekulare Chemie, Georg-August-Universitat Goettingen

* Address correspondence to: E-mail: syang1{at}gwdg.de

Abstract

Haloperidol is known as an antagonist of dopamine D2 receptors. It also blocks a variety of ion channels, however, at concentrations above the therapeutic range. Reduced-haloperidol, one of the main metabolites of haloperidol, has been reported to accumulate in certain tissues, particularly in brain cortex and it might produce the pharmacological effects associated with haloperidol treatment. In this study we assessed the effect of reduced-haloperidol and other related compounds on native delayed-rectifier potassium channels (KDR) in mouse cortical neurons by using the whole-cell patch-clamp technique. Although reduced-haloperidol has much lower affinity to D2 receptors than haloperidol, the IC50 of reduced-haloperidol to block KDR currents was 4.4 µM, similar to its parent compound. The binding site of reduced-haloperidol is on the cytoplasmic side of the channel, as its quaternary derivative preferentially inhibited the currents from intracellular side. 4-Chlorophenyl-4-hydroxypiperidine (4C4HP) is the active fragment of haloperidol since other compounds containing this moiety, including L741-626 and loperamide, also blocked KDR channels. The potency of the 4C4HP fragment positively correlated with the hydrophobicity index (clogP) of the compounds tested. We conclude that reduced-haloperidol is a KDR channel blocker, although it does not interfere with the normal channel function at a clinically relevant concentration.


Key words: clogP, haloperidol, loperamide, metabolites, open-channel block, voltage-activated potassium channels


This article has been cited by other articles:


Home page
 J. Neurophysiol.Home page
D. V. Vasilyev, Q. Shan, Y. Lee, S. C. Mayer, M. R. Bowlby, B. W. Strassle, E. J. Kaftan, K. E. Rogers, and J. Dunlop
Direct Inhibition of Ih by Analgesic Loperamide in Rat DRG Neurons
J Neurophysiol, May 1, 2007; 97(5): 3713 - 3721.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2005 by the American Society for Pharmacology and Experimental Therapeutics.