基于DA/5-HT多靶标作用机制的延胡索乙素衍生物的设计及其抗精神分裂症作用研究

The pathogenesis of schizophrenia relates to various neurotransmitters in brain. Most of the launched anti-schizophrenia drugs are dopamine receptor D2 antagonist or D2/5-HT2A dual antagonist, which has limited cognition improvement and adverse effects such as weight gain. In our previously research, some analogues of tetrahydroberberine (THPB) have multi-target effect as D1 agonist/D2 antagonist/5-HT1A partial agonist. Encouraged by this result, we plan to find novel potential anti-schizophrenia small molecular which have high-potential and suitable pharmacokinetic properties. The further study includes: 1. SAR of analogues of THPB; 2. Combine the structure of THPB analogues and launched small molecular having D2/5-HT2A antagonistic effect to design molecular having D1/5-HT1A agonistic and D2/5-HT2A antagonistic effect; 3. The effect of D1/5-HT1A agonism on cognition and the balance of DA system in brain; 4. Structure optimization of THPBs to improve its metabolic stability.

精神分裂症发病机制是一个涉及脑内多种神经递质的病理生理过程。现有药物多为单纯D2拮抗剂或D2/5-HT2A拮抗剂，对精神分裂症认知功能的改善有限，且有代谢副作用。前期研究发现，天然产物延胡索乙素、千金藤啶碱等四氢原小檗碱类化合物（THPB）具有D1激动/D2拮抗/5-HT1A部分激动作用，本课题将在此基础上，深入研究THPB类化合物对D1/D2/5-HT1A多个靶标的构效关系；同时，拟将THPB类的药效团与D2/5-HT2A拮抗剂类药物的药效团进行拼接，设计、合成一类新的同时具有D1/5-HT1A激动、D2/5-HT2A拮抗多靶点作用机制的化合物；并深入探讨D1激动和5-HT1A激动对平衡脑内DA系统的作用以及对认知功能的影响；并针对含酚羟基的THPB类化合物体内代谢稳定性差的问题，进行结构修饰，以期获得一类具有高体内外活性、良好药代动力学性质的新型抗精神分裂症药物分子。

以天然产物延胡索乙素（l-THP）、千金藤啶碱（l-SPD）为先导，以多巴胺受体D1/D2及5-羟色胺受体5-HT1A为目标靶点，设计合成了多个系列的化合物。部分化合物具有D2部分激动活性和D1拮抗活性，同时对5-HT1A受体具有较强亲和力。部分关键中间体使用了不对称催化的方法进行手性合成。在测试化合物对D1/D2/5-HT1A受体的亲和活性及拮抗或激动活性，并对其活性数据进行评价，总结其构效关系，并且在体内模型上测试活性较高的化合物对精神分裂症阳性症状和阴性症状的改善作用，同时关注了部分化合物在镇痛、镇静催眠方面的体内药效；并探讨多巴胺D2受体部分激动/的受体拮抗活性与体内药效活性之间的关系；化合物TPN156表现出高活性，体内药效明确，毒性小，药代性质好，成药性良好，值得深入研究开发。