title: Identification of a new functional target of haloperidol metabolite: implications for a receptor-independent role of 3-(4-fluorobenzoyl) propionic acid.
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.
authors.affiliation: Department of Life Science, Division of Molecular and Life Science, Pohang University of Science and Technology, Kyungbuk, South Korea.
authors.forename: Hyeon Soo
authors.initials: HS
authors.lastname: Kim
authors.forename: Minseok
authors.initials: M
authors.lastname: Song
authors.forename: Sanatombi
authors.initials: S
authors.lastname: Yumkham
authors.forename: Jang Hyun
authors.initials: JH
authors.lastname: Choi
authors.forename: Taehoon
authors.initials: T
authors.lastname: Lee
authors.forename: Joseph
authors.initials: J
authors.lastname: Kwon
authors.forename: Sung Jae
authors.initials: SJ
authors.lastname: Lee
authors.forename: Jong-In
authors.initials: JI
authors.lastname: Kim
authors.forename: Kang-Woo
authors.initials: KW
authors.lastname: Lee
authors.forename: Pyung-Lim
authors.initials: PL
authors.lastname: Han
authors.forename: Seung Woo
authors.initials: SW
authors.lastname: Shin
authors.forename: Ja-Hyun
authors.initials: JH
authors.lastname: Baik
authors.forename: Yong Sik
authors.initials: YS
authors.lastname: Kim
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Ryu
authors.forename: Pann-Ghill
authors.initials: PG
authors.lastname: Suh
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002375:Catalepsy / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D018492:Dopamine Antagonists / Q000378:metabolism / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D006220:Haloperidol / Q000378:metabolism* / Q000494:pharmacology*; D048369:MAP Kinase Kinase 1 / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011422:Propionates / Q000378:metabolism* / Q000494:pharmacology*; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000378:metabolism
chemical_list: D018492:Dopamine Antagonists; D004791:Enzyme Inhibitors; D011422:Propionates; D017448:Receptors, Dopamine D2; C080346:beta-(4-fluorobenzoyl)propionic acid; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D006220:Haloperidol