Identification of a new functional target of haloperidol metabolite: implications for a receptor-independent role of 3-(4-fluorobenzoyl) propionic acid.
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.
Kim
Hyeon Soo
HS
Department of Life Science, Division of Molecular and Life Science, Pohang University of Science and Technology, Kyungbuk, South Korea.
Song
Minseok
M
Yumkham
Sanatombi
S
Choi
Jang Hyun
JH
Lee
Taehoon
T
Kwon
Joseph
J
Lee
Sung Jae
SJ
Kim
Jong-In
JI
Lee
Kang-Woo
KW
Han
Pyung-Lim
PL
Shin
Seung Woo
SW
Baik
Ja-Hyun
JH
Kim
Yong Sik
YS
Ryu
Sung Ho
SH
Suh
Pann-Ghill
PG
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
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