Pharmacological actions of a novel and selective dopamine D3 receptor antagonist, KCH-1110.
1-(2-ethoxy-phenyl)-4-[3-(3-thiophen-2-yl-isoxazolin-5-yl)-propyl]-piperazine (KCH-1110), has a high affinity for human dopamine D3 (hD3) receptor (Ki=1.28 nM) with about 90-fold selectivity over the human dopamine D2L (hD2L) receptor. Antipsychotic or antidopaminergic activity of KCH-1110 was investigated in the models for the positive symptoms of schizophrenia, apomorphine-induced climbing and cocaine-induced hyperlocomotion, in mice. Intraperitoneal (i.p.) or oral (p.o.) administration of KCH-1110 potently inhibited the apomorphine-induced cage climbing without any rotarod ataxia in mice. Cocaine-induced hyperactivity was also antagonised by KCH-1110. In addition, KCH-1110 attenuated the hypothermia induced by a selective dopamine D3 agonist, 7-OH-DPAT in mice. KCH-1110 did not induce catalepsy in mice, but at much higher doses only a slight catalepsy response was shown. Although high doses of KCH-1110 significantly enhanced serum prolactin secretion in rats, low dose of KCH-1110 did not increase prolactin levels in rats. The present studies, therefore, suggest that KCH-1110 is a potent and relatively selective dopamine D3 receptor antagonist with antipsychotic actions.
Park
Woo-Kyu
WK
Pharmaceutical Screening Research Team, Korea Research Institute of Chemical Technology, 100 Jang-Dong, Yusong-Gu, Daejon 305-343, South Korea.
Jeong
Daeyoung
D
Yun
Cheol-Won
CW
Lee
Sunghou
S
Cho
Heeyeong
H
Kim
Gun-Do
GD
Koh
Hun Yeong
HY
Pae
Ae Nim
AN
Cho
Yong Seo
YS
Choi
Kyung Il
KI
Jung
Ji Young
JY
Jung
Sun Ho
SH
Kong
Jae Yang
JY
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001549:Benzamides / Q000378:metabolism; D001667:Binding, Competitive; D001831:Body Temperature / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced; D002460:Cell Line; D003024:Clozapine / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D007035:Hypothermia / Q000139:chemically induced; D007555:Isoxazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D011388:Prolactin / Q000097:blood; D011597:Psychomotor Performance / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D050637:Receptors, Dopamine D3; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D013876:Thiophenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014316:Tritium
C488454:1-(2-ethoxyphenyl)-4-(3-(3-thiophen-2-ylisoxazolin-5-yl)propyl)piperazine; D014150:Antipsychotic Agents; D001549:Benzamides; C493593:DRD3 protein, human; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; C493594:Drd3 protein, mouse; C493595:Drd3 protein, rat; D007555:Isoxazoles; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; D014316:Tritium; D011388:Prolactin; D003042:Cocaine; D003024:Clozapine; D006220:Haloperidol; C030265:nemonapride; C031349:7-hydroxy-2-N,N-dipropylaminotetralin