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.