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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
Author(s) -
Kim Hyeon Soo,
Song Minseok,
Yumkham Sanatombi,
Choi Jang Hyun,
Lee Taehoon,
Kwon Joseph,
Lee Sung Jae,
Kim JongIn,
Lee KangWoo,
Han PyungLim,
Shin Seung Woo,
Baik JaHyun,
Kim Yong Sik,
Ryu Sung Ho,
Suh PannGhill
Publication year - 2006
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.04108.x
Subject(s) - haloperidol , metabolite , identification (biology) , chemistry , receptor , stereochemistry , biochemistry , pharmacology , neuroscience , psychology , biology , dopamine , botany
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.