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Identification of a new functional target of haloperidol metabolite: implications for a receptor-independent role of 3-(4-fluorobenzoyl) propionic acid

Cited 7 time in Web of Science Cited 7 time in Scopus
Authors
Kim, Hyeon Soo; Song, Minseok; Yumkham, Sanatombi; Choi, Jang Hyun; Lee, Taehoon; Kwon, Joseph; Lee, Sung Jae; Kim, Jong-In; Lee, Kang-Woo; Han, Pyung-Lim; Shin, Seung Woo; Baik, Ja-Hyun; Kim, Yong Sik; Ryu, Sung Ho; Suh, Pann-Ghill
Issue Date
2006-10-13
Publisher
Wiley-Blackwell
Citation
J Neurochem. 2006 Oct;99(2):458-69.
Keywords
AnimalsBrain/drug effects/metabolismCatalepsy/chemically induced/metabolism/physiopathologyCell Line, TransformedDisease Models, AnimalDopamine Antagonists/metabolism/pharmacologyEnzyme Inhibitors/pharmacologyExtracellular Signal-Regulated MAP Kinases/drug effects/metabolismHaloperidol/*metabolism/*pharmacologyMAP Kinase Kinase 1/drug effects/metabolismMaleMiceMice, Inbred C57BLMolecular StructureMotor Activity/drug effects/physiologyNeurons/*drug effects/metabolismPhosphorylation/drug effectsPropionic Acids/*metabolism/*pharmacologyReceptors, Dopamine D2/*drug effects/metabolism
Abstract
Haloperidol, a dopamine D2 receptor blocker, is a classical neuroleptic drug that elicits extrapyramidal symptoms. Its metabolites include 3-(4-fluorobenzoyl) propionic acid (FBPA) and 4-(4-chlorophenyl)-4-piperidinol (CPHP). Until now, the biological significance of these metabolites has remained largely unknown. Here, we report that the administration of FBPA to mice effected a suppression of locomotor activity and induced catalepsy in a manner similar to that observed with haloperidol, whereas CPHP had no significant effects. Neither of these two metabolites, however, exhibited any ability to bind to the dopamine D2 receptor. FBPA blocked dopamine-induced extracellular signal-regulated kinase 1/2 phosphorylation, and it specifically affected mitogen-activated protein kinase kinase (MEK)1/2 activity in hippocampal HN33 cells. Moreover, FBPA was capable of direct interaction with MEK1/2, and inhibited its activity in vitro. We demonstrated the generation of haloperidol metabolites within haloperidol-treated cells by mass spectrometric analyses. Collectively, our results confirm the biological activity of FBPA, and provide initial clues as to the receptor-independent role of haloperidol.
ISSN
0022-3042 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17029599

https://hdl.handle.net/10371/29381
DOI
https://doi.org/10.1111/j.1471-4159.2006.04108.x
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College of Medicine/School of Medicine (의과대학/대학원)Psychiatry (정신과학전공)Journal Papers (저널논문_정신과학전공)
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