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

Abstract

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.

• Authors: Woo-Kyu Park, Daeyoung Jeong, Cheol-Won Yun, Sunghou Lee, Heeyeong Cho, Gun-Do Kim, Hun Yeong Koh, Ae Nim Pae, Yong Seo Cho, Kyung Il Choi, Ji Young Jung, Sun Ho Jung, Jae Yang Kong
• Journal: Pharmacological research (Pharmacol Res) Vol. 48 Issue 6 Pg. 615-22 (Dec 2003) ISSN: 1043-6618 [Print] Netherlands
• PMID: 14527827 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-(2-ethoxyphenyl)-4-(3-(3-thiophen-2-ylisoxazolin-5-yl)propyl)piperazine
• Antipsychotic Agents
• Benzamides
• DRD3 protein, human
• Dopamine Agonists
• Dopamine Antagonists
• Dopamine D2 Receptor Antagonists
• Drd3 protein, mouse
• Drd3 protein, rat
• Isoxazoles
• Receptors, Dopamine D2
• Receptors, Dopamine D3
• Tetrahydronaphthalenes
• Thiophenes
• Tritium
• Prolactin
• Cocaine
• Clozapine
• Haloperidol
• nemonapride
• 7-hydroxy-2-N,N-dipropylaminotetralin

Topics

• 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, metabolism, pharmacology)
• Male
• Mice
• Motor Activity (drug effects)
• Prolactin (blood)
• Psychomotor Performance (drug effects)
• Radioligand Assay
• Rats
• Rats, Sprague-Dawley
• Receptors, Dopamine D2 (genetics, metabolism)
• Receptors, Dopamine D3
• Tetrahydronaphthalenes (pharmacology)
• Thiophenes (chemistry, metabolism, pharmacology)
• Tritium