基于非组氨H1受体作用的多靶点抗精神分裂症化合物设计合成及活性研究

The main shortcoming of antipsychotic agents are the inefficient improvement of cognitive function and severe sedation. It is believed that antagonism of central histamine Hl-receptors resulted in sedation, which intervened the evaluation of cognitive improvement in animal models. Nevertheless, there is a great challenge for the discovery of antipsychotic candidates without H1 effects. Compounds acting on D2/D3/5-HT2A receptors with proper D3R preferring, may alleviate cognitive deficiency. However, ligands with such pharmacologic features were barely reported at present. In our continuing efforts on developing novel antipsychotic agents targeting D2, D3 and 5-HT2A receptors, SIPI6450-like compounds were designed, synthesized, and demonstrated with nanomolar affinity and specificity for D3R/D2R as well as high affinity for 5-HT2A receptors and low affinity for H1 receptors. On the basis of the previous work, series of SIPI6450-like derivatives targeting D2, D3 and 5-HT2A receptors as well as proper D3/D2 subtype selectivity, and low H1 affinity will be designed, synthesized and structurally optimized. The structure and activity relationship will be discussed for compounds with the characteristics of high affinity for D2, D3 and 5-HT2A receptors, proper D3/D2 subtype selectivity and low H1 effect. Meanwhile, the preferred ones will be tested in different animal models to investigate the improvement of cognitive deficiency. Our work will lay a foundation and provide a theoretical guide for the discovery of novel multi-target antipsychotic agents with proper D3 receptor selectivity and without H1 receptor effect.

现有抗精神分裂药无认知改善及具强的镇静副作用。研究表明，拮抗组胺H1受体所致镇静作用干预认知改善的行为学评价，甚至加重认知损害。非作用于H1、避免镇静作用对认知改善的负效应为该类新药发现的难点和关键。拮抗D2/D3/5-HT2A受体、兼具D3/D2亚型选择性，具同时改善认知的广谱抗精神分裂作用。然而具该药靶特征，且无H1受体作用的活性分子鲜有报道。本课题前期发现SIPI6450等化合物对D2/D3/5-HT2A具纳摩尔级亲和力、合理D3/D2选择性及低的H1作用。本申请课题将以该类化合物为先导，进一步优化设计合成作用于D2/D3/5-HT2A、兼具D3/D2亚型合理选择性及非H1作用的高活性分子，讨论具D2/D3/5-HT2A高亲和力和D3/D2合理选择性特征的化合物与H1作用的构效关系，以发现具认知障碍改善作用的高效低副多靶点抗精神分裂活性分子，为该领域新药的研究提供科学参考和经验借鉴。

精神分裂症为精神性疾病中最严重、危害最大的一种。目前，市售及临床在研抗精神分裂症药物几无认知障碍改善作用，且上市药物大多存在强的镇静副作用。研究表明，拮抗组胺H1受体所致镇静作用将干预认知改善的行为学评价，甚至加重认知损伤。非作用于H1受体、避免或降低镇静作用对认知改善的负效应为该类新药发现的难点和关键。临床及临床前研究结果显示，拮抗D2/D3/5-HT2A受体、兼具D3/D2受体亚型选择性，具备同时改善认知障碍的广谱抗精神分裂作用。然而，具该类靶点作用特征，且无H1受体作用的活性分子鲜有报道。本课题组前期针对D2/D3/5-HT2A受体拮抗剂研究，发现SIPI6450等化合物对D3/D2受体具高亲和力（亚纳摩尔级）及合理选择性，对5-HT2A受体亦具强亲和力，同时对H1受体亲和力低，具深入研究价值。本课题基于上述发现，以SIPI6450等化合物为先导结构，结合计算机辅助药物设计，进一步多轮优化设计合成数十个作用于D2/D3/5-HT2A受体、兼具D3/D2受体亚型合理选择性及非H1受体作用的分子，确证了化合物的化学结构，讨论了受体/配体作用的相应构效关系，分析了影响化合物与H1受体亲和力的关键药效团及氨基酸残基，并确定了体外活性较优的分子。体外活性优选分子经初步动物体内药效、体内外代谢特性、初步安全性评价等比较性研究，发现了具进一步研究价值的新型多靶点抗精神分裂症活性分子SIPI10499。本课题后续将继续针对该化合物进行深入、系统的成药性评价研究，为新型抗精神分裂症候选新药结构的确定奠定研究基础。.通过本项目的研究，共发表3篇SCI研究论文和1篇中文核心期刊研究论文，并申请2项国内外发明专利。本项目的研究结果可为定向设计合成具认知障碍改善作用的高效低副多靶点抗精神分裂活性分子提供借鉴。

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