具有NMDA受体NR2B选择性拮抗活性的依达拉奉衍生物的发现

Cerebral ischemia triggers a complex series of biochemical and molecular mechanisms that impairs the neurologic functions through breakdown of cellular integrity mediated by excitotoxic glutamatergic signalling, ionic imbalance, free-radical reactions, etc. Generally, these processes are complex diseases which must be treated with a cocktail of drugs. An alternative could be the use of co-drugs, namely single products active at more than one target, and consequently exercising more than one action simultaneously. In the preliminary study, we built the pharmacophore of NR2B subtype-selective NMDA antagonists, and designed a novel series of NR2B subtype-selective NMDA antagonists, which exhibited certain neuroprotective effects. In particular, among these compounds we designed, DZH-1 exhibited excellent neuroprotective activities in vitro and furthermore significantly reduced infarct area in vivo rat focal cerebral ischemic animal model. Edaravone, a free radical scavenger, was developed in Japan for treating of patients in the acute stage of cerebral thrombosis or embolism, and has been reported to be effective also in the acute stage of stroke. Edaravone displays potent antioxidant properties, and consequently it might be useful in managing other pathological processes involving oxidative stress. The objective of this study is to design and synthesize a new class of co-drugs by combining antioxidant Edaravone with moieties of NR2B subtype-selective NMDA antagonists. The design of the co-drugs is achieved by fusing, or joining through appropriate linkers, generally two drugs, or crucial parts of them. The title products display the dual action of antioxidant and NR2B subtype-selective NMDA antagonistic activities. They are potentially useful in treating acute cerebral ischemia.

缺血性脑损伤机制的多重性和"瀑布效应"决定了单一神经保护剂治疗不能很好地奏效,具有多重作用机制的神经保护剂，有望成为安全有效的脑卒中治疗药物。在前期的研究中，我们构建了NMDA受体NR2B选择性拮抗剂的药效团模型，设计合成了100多个新型NMDA受体NR2B选择性拮抗剂, 经药理活性筛选和药效学评价，发现化合物DZH-1可显著延长双侧颈总动脉结扎小鼠的存活时间，明显降低大鼠海马CA1区NR2B mRNA表达，对MCAO脑梗塞具有较好的保护作用。依达拉奉是第一个成功地用于急性脑缺血治疗的自由基清除剂，据文献调研，目前尚无依达拉奉-NMDA受体NR2B选择性拮抗剂孪药的文献报道。本项目拟选择DZH-1和依达拉奉为先导化合物，将依达拉奉与NMDA受体NR2B选择性拮抗剂进行拼合，设计具有双重作用机制的抗缺血性脑卒中孪药，为研究开发具有自主知识产权的抗脑卒中创新药物及孪药的设计应用提供有益的参考。

缺血性脑卒中是当今致死率和致残率最高的疾病之一，然而除了早期使用的溶栓药和少数抗氧化剂/自由基清除剂外，目前临床尚缺乏疗效明确、安全性好的药物。重要的原因就是单一神经保护剂只作用于脑卒中某一病理机制环节，而缺血性脑卒中涉及多种病理机制，各种机制协同作用，共同导致病情加重。具有多重作用机制的神经保护剂，有望成为安全有效的脑卒中治疗药物。在前期的研究中，我们构建了NMDA受体NR2B选择性拮抗剂的药效团模型，设计合成了100多个新型NMDA受体NR2B选择性拮抗剂, 经药理活性筛选和药效学评价，发现化合物DZH-1可显著延长双侧颈总动脉结扎小鼠的存活时间，明显降低大鼠海马CA1区NR2B mRNA表达，对MCAO脑梗塞具有较好的保护作用。依达拉奉是第一个成功地用于急性脑缺血治疗的自由基清除剂，据文献调研，目前尚无依达拉奉-NMDA受体NR2B选择性拮抗剂孪药的文献报道。本项目选择DZH-1和依达拉奉为先导化合物，将依达拉奉与NMDA受体NR2B选择性拮抗剂进行拼合，设计具有双重作用机制的抗缺血性脑卒中孪药，为研究开发具有自主知识产权的抗脑卒中创新药物及孪药的设计应用提供有益的参考。本项目设计、合成了四类目标化合物82个，均通过1H NMR、13C NMR和HRMS进行结构确证；对部分目标化合物进行生物活性测试和药效学评价初步评价；同时进行了单晶的培养与解析；在进行作用机制探讨研究时，发现前期合成的具有抗缺血性脑中风活性的部分化合物具有抗细胞凋亡活性，我们进行了基于Caspase-3结构的药效团构建、基于配体的药效团构建以及先导化合物与Caspase-3活性位点的分子对接。初步验证了孪药设计方法的可行性和可靠性，为设计、合成新型抗缺血性脑卒中孪药提供了理论依据。