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

Pharmacol Res. 2003 Dec;48(6):615-22. doi: 10.1016/s1043-6618(03)00242-1.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • 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