Background: Schizophrenia is a disorder with complex etiology with hyperdopaminergia as the leading underlying cause. Atypical antipsychotics are the agents which do not give rise to significant extrapyramidal side effects and are more effective against negative symptoms of schizophrenia.

Introduction: A new series of chloro-substituted substituted aryloxypiperazine derivatives and their indole based derivatives was designed and evaluated for atypical antipsychotic activity based on established models for combined dopaminergic and serotonergic antagonism.

Methods: The present series of compounds were designed based on 3D similarity studies, synthesized and evaluated for atypical antipsychotic activity in animal models for combined dopaminergic and serotonergic antagonism. The blood-brain barrier penetration potential was assessed from theoretical log BB values computed through an online software program.

Results: Theoretical ADME profiling of the designed compounds based on selected physicochemical parameters suggested excellent compliance with Lipinski’s rules. The log BB values obtained for the compounds suggested a good potential for brain permeation. Indole substitution contributed towards an improved efficacy over aryloxy analogs. Lead compounds showed a potential for combined dopaminergic and serotonergic antagonism.

Conclusion: The 5-methoxy indole based compounds 16 and 17 were identified as the lead compounds displaying a potential atypical antipsychotic profile.

背景：精神分裂症是一种病因复杂的疾病，以高多巴胺痛为主要潜在病因。非典型抗精神病药是不会引起明显的锥体束外副作用且对精神分裂症的阴性症状更有效的药物。

简介：基于建立的多巴胺能和血清素能拮抗联合模型，设计并评估了一系列新的氯取代的芳氧基哌嗪衍生物及其吲哚基衍生物。

方法：基于3D相似性研究设计了本系列化合物，合成并评估了多巴胺能和血清素能联合拮抗作用在动物模型中的非典型抗精神病活性。通过在线软件程序计算的理论log BB值评估了血脑屏障穿透的潜力。

结果：根据选定的理化参数对设计的化合物进行理论上的ADME分析，结果表明其与Lipinski规则完全吻合。这些化合物的log BB值表明脑渗透的潜力很大。与芳氧基类似物相比，吲哚取代有助于提高功效。铅化合物显示出多巴胺能和血清素能联合拮抗作用的潜力。

结论：以5-甲氧基吲哚为基础的化合物16和17被鉴定为显示潜在的非典型抗精神病药物特征的先导化合物。