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KKHA-761, a potent D3 receptor antagonist with high 5-HT1A receptor affinity, exhibits antipsychotic properties in animal models of schizophrenia.

Abstract
KKHA-761, 1-{4-[3-(3,4-dimethoxy-phenyl)-isoxazol-5-yl]-butyl}-4-(2-methoxy-phenyl)-piperazine, has a high affinity (Ki=3.85 nM) for human dopamine D3 receptor with about 70-fold selectivity over the human dopamine D(2L) receptor (Ki=270 nM). KKHA-761 also showed high affinity for cloned human 5-HT1A receptor (Ki=6.4 nM). KKHA-761 exhibited D3 and 5-HT1A receptor antagonist activities in vitro, reversing dopamine- or 5-HT-mediated stimulation of [35S]GTPrS binding. The in vivo pharmacological profile of KKHA-761 was compared with both typical and atypical antipsychotics including clozapine and haloperidol. Apomorphine-induced dopaminergic behavior, cage climbing, in mice was potently blocked by a single administration (i.p.) of KKHA-761 (ID50=4.06 mg/kg) or clozapine (ID50=4.0 mg/kg). Cocaine- or MK-801-induced hyperactivity in animals was markedly inhibited by KKHA-761 or clozapine. In addition, KKHA-761 significantly reversed the disruption of prepulse inhibition (PPI) produced by apomorphine in mice, indicating the antidopaminergic or antipsychotic activity of KKHA-761 in mice. However, KKHA-761 was inactive in the forced swimming behavioral despair model in mice, suggesting lack of antidepressant properties. KKHA-761 attenuated the hypothermia induced by a selective dopamine D3 agonist, 7-OH-DPAT, in mice, whereas clozapine enhanced it. Moderate doses of both KKHA-761 and clozapine did not increase serum prolactin levels in rats. Lower doses of, however, haloperidol significantly increased prolactin secretion. KKHA-761 did not induce cataleptic response up to 20 mg/kg, but significant catalepsy was shown at lower doses of clozapine and haloperidol. Furthermore, KKHA-761 showed a low incidence of rotarod ataxia (TD50=34.4 mg/kg, i.p.) in mice. The present results, therefore, suggest that KKHA-761 is a potent antipsychotic agent with combined dopamine D3 and serotonin 5-HT1A receptors modulation activity, which may further enhance its therapeutic potential for anxiety, psychotic depression, and other related disorders.
AuthorsWoo-Kyu Park, Daeyoung Jeong, Heeyeong Cho, Seong Jin Lee, Mi Young Cha, Ae Nim Pae, Kyung Il Choi, Hun Yeong Koh, Jae Yang Kong
JournalPharmacology, biochemistry, and behavior (Pharmacol Biochem Behav) Vol. 82 Issue 2 Pg. 361-72 (Oct 2005) ISSN: 0091-3057 [Print] United States
PMID16216322 (Publication Type: Journal Article)
Chemical References
  • Antipsychotic Agents
  • Dopamine Uptake Inhibitors
  • Ion Channels
  • Isoxazoles
  • KKHA-761
  • Piperazines
  • Receptors, Dopamine D1
  • Receptors, Dopamine D3
  • Serotonin Receptor Agonists
  • Receptor, Serotonin, 5-HT1A
  • Receptors, Dopamine D4
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Spiperone
  • Prolactin
Topics
  • Animals
  • Antipsychotic Agents
  • Body Temperature (drug effects)
  • Catalepsy (chemically induced, psychology)
  • Cell Line
  • Dopamine Uptake Inhibitors (pharmacology)
  • Guanosine 5'-O-(3-Thiotriphosphate) (metabolism)
  • Humans
  • Ion Channels (drug effects, metabolism)
  • Isoxazoles (pharmacokinetics, pharmacology)
  • Male
  • Mice
  • Mice, Inbred ICR
  • Piperazines (pharmacokinetics, pharmacology)
  • Postural Balance (drug effects)
  • Prolactin (metabolism)
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT1A (drug effects, metabolism)
  • Receptors, Dopamine D1 (metabolism)
  • Receptors, Dopamine D3 (antagonists & inhibitors)
  • Receptors, Dopamine D4 (drug effects, metabolism)
  • Reflex, Startle (drug effects)
  • Schizophrenia (drug therapy)
  • Schizophrenic Psychology
  • Serotonin Receptor Agonists (pharmacology)
  • Spiperone (metabolism)
  • Swimming (psychology)

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