吲哚生物碱koumine的全合成及基于理性设计的药物化学研究

神经病理性疼痛（NP）是一种发病率高而缺乏有效治疗药物的慢性病症。目前用于缓解NP的传统镇痛药物因无法直接作用于调控NP的靶点而普遍存在疗效差和副作用明显等缺点。近期研究表明α3甘氨酸受体（GlyRα3）在NP发生中发挥关键调控机制，是重要的NP治疗靶标，而天然产物koumine可以通过提高GlyRα3的活性发挥靶向性镇痛作用。由于koumine具有复杂笼状结构和多手性中心，合成工作极具挑战，当前药学研究仅限于单个分子，而构效关系和优化研究尚未见报道。基于此，本项目拟开展如下研究：发展新颖的串联反应和合成策略，快速构建koumine核心笼状骨架，实现高效全合成和多样化衍生；基于GlyRα3靶点并结合生物活性评价对koumine类分子进行理性设计、改造，探索构效关系和药效团。通过综合上述研究，期望获得镇痛活性高、成药性提升的靶向GlyRα3苗头化合物，为开发针对新靶标的NP治疗药物奠定基础。

Neuropathic pain (NP) is a chronic disease with high incidence and lacks effective drugs. Clinically, traditional analgesic drugs are generally utilized to relieve NP. Yet these treatments are usually plagued by poor efficacy and severe side effects, as the result of the incapability to specifically function on the NP’s modulating targets. Recent studies have disclosed that the α3 glycine receptor (GlyRα3) plays a key regulatory role in the occurrence of NP and hence has become a promising target for NP therapy. The natural product koumine exerts impressive analgesic effects by increasing the activity of GlyRα3. However, the synthesis and derivations of koumine, which possesses a complex cage scaffold and multiple chiral centers, are extremely challenging. Consequently, current pharmaceutical research only focused on koumine itself, which was isolated from the plants, while the structure-activity relationship (SAR) and optimization studies remain undisclosed. In light of this situation, this project sets out to: 1) develop new tandem reactions and synthetic strategies to quickly construct the cage-shaped core, and accomplish total synthesis and diversified derivation of koumine; 2) conduct rational design and structure optimization based on the GlyRα3 structure and biological evaluation to achieve SAR and pharmacophore clues of koumines. Based on these investigations, improved agents that target GlyRα3 with high analgesic activity and improved druggability are expected to obtain, thus laying the foundation for developing novel NP therapeutic drugs with the new target.