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首页> 外文期刊>Pharmacology, Biochemistry and Behavior >KKHA-761, a potent D3 receptor antagonist with high 5-HT1A receptor affinity, exhibits antipsychotic properties in animal models of schizophrenia.
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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.

机译：KKHA-761是一种具有高5-HT1A受体亲和力的有效D3受体拮抗剂，在精神分裂症动物模型中具有抗精神病特性。

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摘要

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 otherrelated disorders.
机译：KKHA-761，1- {4- [3-（3,4-二甲氧基-苯基）-异恶唑-5-基]-丁基} -4-（2-甲氧基-苯基）-哌嗪，具有高亲和力（Ki对于人多巴胺D3受体，其选择性为3.85 nM），而对人多巴胺D（2L）受体的选择性约为70倍（Ki = 270 nM）。 KKHA-761还显示出对克隆的人5-HT1A受体的高度亲和力（Ki = 6.4 nM）。 KKHA-761在体外表现出D3和5-HT1A受体拮抗剂活性，逆转了多巴胺或5-HT介导的[35S] GTPrS结合刺激。将KKHA-761的体内药理特性与典型和非典型抗精神病药（包括氯氮平和氟哌啶醇）进行了比较。阿扑吗啡诱导的多巴胺能行为，笼子爬升被单次施用（i.p.）KKHA-761（ID50 = 4.06 mg / kg）或氯氮平（ID50 = 4.0 mg / kg）强力阻断。可卡因或MK-801诱导的动物活动亢进明显被KKHA-761或氯氮平抑制。此外，KKHA-761可显着逆转阿扑吗啡对小鼠产生的前脉冲抑制（PPI）的破坏，表明KKHA-761在小鼠中具有抗多巴胺能或抗精神病活性。然而，KKHA-761在小鼠强迫游泳行为绝望模型中没有活性，表明缺乏抗抑郁特性。 KKHA-761在小鼠中减弱了由选择性多巴胺D3激动剂7-OH-DPAT诱导的体温过低，而氯氮平却增强了这种低温。适量的KKHA-761和氯氮平均未增加大鼠血清催乳素水平。但是，较低剂量的氟哌啶醇可显着增加催乳素分泌。高达20 mg / kg时，KKHA-761不会诱发抗感性反应，但是在较低剂量的氯氮平和氟哌啶醇下，却表现出明显的僵直性。此外，KKHA-761在小鼠中显示出轮状共济失调的低发生率（TD50 ＝ 34.4mg / kg，i.p。）。因此，目前的结果表明，KKHA-761是一种有效的抗精神病药，具有多巴胺D3和5-羟色胺5-HT1A受体组合的调节活性，可进一步增强其治疗焦虑症，精神病性抑郁症和其他相关疾病的潜力。

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