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

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.

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。

作为临床最为常见的症状之一，疼痛已严重影响广大患者的生活质量。目前，临床用于疼痛治疗缓解的药物主要包括非甾体类抗炎药、中枢阿片受体激动剂等。然而，上述传统镇痛药物具有成瘾性强、致幻、对胃肠道刺激性强等毒副作用，这严重地制约了临床对于疼痛的缓解及治疗。因此，寻找新的镇痛药物作用靶点，开发无成瘾性、低毒副作用的新型镇痛药物已成为当今药物研究领域的热点及难点。相较于目前临床镇痛一线用药—阿片受体激动剂、环氧合酶2（COX-2）抑制剂，瞬时受体电位香草酸亚型1（TRPV1）小分子拮抗剂具有无成瘾性、针对难以缓解的神经性疼痛具有良好治疗效果等优点。基于2-（3-氟-4-甲磺酰胺基苯基）丙酰胺类和6,6-稠杂环脲类TPRV1小分子拮抗剂的生物活性、热力学溶解度等测试结果，设计并合成了A/B区分别为N-(3-氟-4-甲磺酰胺甲苯基)脲类、异喹啉-5-基脲类及异喹啉-8-基脲类TPRV1拮抗剂。相关测试结果表明，部分化合物在保持优良受体亲合力的同时能够有效克服前期所设计TPRV1拮抗剂所具有的导致体核温度增高、生物利用度较差等缺陷，具有成为新型无成瘾性镇痛候选药物的可能性。