基于TRPV1三维结构的新型镇痛药物的设计、合成及镇痛作用研究

项目名称： 基于TRPV1三维结构的新型镇痛药物的设计、合成及镇痛作用研究

项目编号： No.81502927

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 孙伟

作者单位： 沈阳药科大学

项目金额： 17.9万元

中文摘要： 作为一类新的镇痛药物作用靶点，瞬时受体电位香草酸亚型1（TRPV1）在疼痛信号的传递及感知过程中发挥重要作用。因此，开发该受体的特异性拮抗剂已成为无成瘾性新型镇痛药物开发的又一热点。基于RTX的构效关系，本课题前期通过药效团模型的构建设计并合成了一系列2-(3-氟-4-甲磺酰胺基苯基)丙酰胺类和6,6-稠杂环脲类化合物。生物活性测试及分子模拟研究表明，其能够与位于TM3/4活性腔形成良好的匹配，且部分衍生物表现出良好的受体拮抗性及体内镇痛作用。鉴于上述两类化合物具有较差的药代动力学性质及部分拮抗剂诱导体核温度增高，以前期分子模拟结果和构效关系为指导，运用“共生型”设计法，进行衍生物设计与合成，进而以生物活性、热力学溶解度等测试结果修正化合物设计，建立准确的药效团和构效关系，阐明TRPV1在疼痛和体温调节通路中的作用，力争获得具有自主知识产权、安全有效的新型镇痛候选药物。

中文关键词： 镇痛药物；瞬时受体电位香草酸亚型1；特异性拮抗剂；药效团；构效关系

英文摘要： As a new target for the treatment of pain, transient receptor potential vanilloid 1 (TRPV1) plays an important role in the transmission and perception of pain signals. Therefore, exploitation of the TRPV1 specific antagonist has become a new hot-point in the development of non-addictive analgesics. Based on the SAR of RTX, 2-(3-fluoro-4-methylsulfonylaminophenyl) propanamide and 6,6-fused heterocyllic urea were designed and synthesized by the construction of pharmacophore model. The results of biological activity assay and molecular modeling demonstrate that these two kinds of compounds could fit well with the binding pocket located at TM3/4. Meanwhile, some derivatives show strong antagonism and analgesic activity in animal pain models. To further optimize the pharmacokinetic properties of these two kinds of compounds and alleviate or eliminate TRPV1-related hyperthermia, the design and synthesis of derivatives will be carried out by using symbiotic approach under the direction of former result of molecular modeling and SAR.The subsequent bioevaluation and thermodynamic solubility test will provide further evidence for derivative design again. Accurate pharmacophore and structure-activity relationship could be established. Meanwhile, the role of TRPV1 in pain and temperature-regulating pathway will be elucidated. The innovative analgesic candidates with independent intellectual property are most likely to be obtained.

英文关键词： analgesics;transient receptor potential vanilloid 1;specific antagonist;pharmacophore;structure-activity relationship