KKHA-761, a new Piperazine

[Alfa]

KKHA-761, a potent D(3) receptor antagonist with high 5-HT(1A) receptor affinity, exhibits antipsychotic properties in animal models of schizophrenia.



Pharmaceutical Screening Research Team, Korea Research Institute of Chemical Technology, (KRICT), 100 Jang-Dong, Yuseong-Gu, Daejon 305-343, Korea.

KKHA-761, 1-{4-[3-(3,4-dimethoxy-phenyl)-isoxazol-5-yl]-butyl}-4-(2-methoxy-phenyl)-piperazine, has a high affinity (K(i)=3.85 nM) for human dopamine D(3) receptor with about 70-fold selectivity over the human dopamine D(2L) receptor (K(i)=270 nM). KKHA-761 also showed high affinity for cloned human 5-HT(1A) receptor (K(i)=6.4 nM). KKHA-761 exhibited D(3) and 5-HT(1A) receptor antagonist activities in vitro, reversing dopamine- or 5-HT-mediated stimulation of [(35)S]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 (ID(50)=4.06 mg/kg) or clozapine (ID(50)=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 D(3) 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 (TD(50)=34.4 mg/kg, i.p.) in mice. The present results, therefore, suggest that KKHA-761 is a potent antipsychotic agent with combined dopamine D(3) and serotonin 5-HT(1A) receptors modulation activity, which may further enhance its therapeutic potential for anxiety, psychotic depression, and other related disorders.