SYNTHESIS AND BIOLOGICAL EVALUATION OF 1-(1,2-BENZISOTHIAZOL-3-YL)PIPERAZINE AND (1,2-BENZISOXAZOL-3-YL)PIPERAZINE DERIVATIVES AS POTENTIAL ANTIPSYCHOTIC AGENTS
SYNTHESIS AND BIOLOGICAL EVALUATION OF 1-(1,2-BENZISOTHIAZOL-3-YL)PIPERAZINE AND (1,2-BENZISOXAZOL-3-YL)PIPERAZINE DERIVATIVES AS POTENTIAL ANTIPSYCHOTIC AGENTS
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DOI：
10.1021/jm00153a010
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发表时间：
1986-03-01
影响因子：
7.3
通讯作者：
TEMPLE, DL
中科院分区：
文献类型：
--
作者：
YEVICH, JP;NEW, JS;TEMPLE, DL
在相关的受体结合分析和行为筛查中，对该系列标题化合物的成员进行了潜在的抗精神病活性测试。讨论了该系列中的结构-活性关系。化合物24(Bmy 13859-1)是一种(1，2-苯并异噻唑-3-基)哌嗪类化合物，由于其在初级中枢神经系统实验中的强效和选择性，被选为进一步研究的对象。它在Sidman回避范式中是活跃的，并在长达7小时的时间内阻断安非他明诱导的狗的刻板行为。在大鼠惊厥测试中缺乏典型的神经镇静剂样作用，以及长期给药后未能产生多巴胺受体超敏反应的化合物S表明，它不应该导致通常与抗精神病药物治疗有关的运动障碍。尽管24对多巴胺能结合部位有很强的亲和力，但它对5-羟色胺受体的更高亲和力表明，5-羟色胺能成分可能与其非典型特征有关。化合物24目前正在进行精神分裂症患者的临床评估。
Members of the series of title compounds were tested for potential antipsychotic activity in relevant receptor binding assays and behavioural screens. Structure-activity relationships within the series are discussed. Compound 24 (BMY 13859-1), a (1,2-benzisothiazol-3-yl)piperazine derivative, was selected for further study because of its potent and selective profile in primary CNS tests. It was active in the Sidman avoidance paradigm and blocked amphetamine-induced stereotyped behavior in dogs for up to 7 h. The compound''s lack of typical neuroleptic-like effects in the rat catalepsy test and its failure to produce dopamine receptor supersensitivity following chronic administration indicate that it should not cause the movement disorders commonly associated with antipsychotic therapy. Although 24 has potent affinity for dopaminergic binding sites, its even greater affinity for serotonin receptors suggests that a serotonergic component may be relevant to its atypical profile. Compound 24 is currently undergoing clinical evaluation in schizophrenic patients.