Pharmacological actions of a novel and selective dopamine D3 receptor antagonist, KCH-1110

• Published in: Pharmacological research 2003-12, Vol.48 (6), p.615-622
• Main Authors: Park, Woo-Kyu, Jeong, Daeyoung, Yun, Cheol-Won, Lee, Sunghou, Cho, Heeyeong, Kim, Gun-Do, Koh, Hun Yeong, Pae, Ae Nim, Cho, Yong Seo, Choi, Kyung Il, Jung, Ji Young, Jung, Sun Ho, Kong, Jae Yang
• Format: Article
• Language: English
• Subjects: Animals; Antipsychotic Agents - pharmacology; Benzamides - metabolism; Binding, Competitive; Body Temperature - drug effects; Catalepsy - chemically induced; Cell Line; Clozapine - pharmacology; Cocaine - pharmacology; Dopamine Agonists - pharmacology; Dopamine Antagonists - pharmacology; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Haloperidol - pharmacology; Humans; Hypothermia - chemically induced; Isoxazoles - chemistry; Isoxazoles - metabolism; Isoxazoles - pharmacology; Male; Mice; Motor Activity - drug effects; Prolactin - blood; Psychomotor Performance - drug effects; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2 - genetics; Receptors, Dopamine D2 - metabolism; Receptors, Dopamine D3; Tetrahydronaphthalenes - pharmacology; Thiophenes - chemistry; Thiophenes - metabolism; Thiophenes - pharmacology; Tritium
• ISSN: 1043-6618
• DOI: 10.1016/S1043-6618(03)00242-1

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.