基于组胺H3受体的新型神经痛药物研究

Neuropathic pain is one of the most difficult clinical syndromes which serious effect human health and its diagnosis and treatment is global hard problem. However, Available clinical therapies have many deficiencies, with slow progress of developing novel drugs, thus developing novel anti-neuropathic pain drugs has great scientific significance and clinical value. Histamine H3 receptor, as a key receptor in center nervous system (CNS) which could modulate the release of various neurotransmitters, is currently one of the most popular target for analgesia of neuropathic pain. On the basis of our previous work, this project aimed to design and synthesis of novel histamine H3 receptor antagonists/inverse agonists by computer-aid drug design (CADD) and classic theory of medicinal chemistry. The designed compounds will be initially characterized by in vitro test, and the high binding affinity H3 receptor antagonists/inverse agonists with good selectivity will then evaluated in in vivo animal pain models and toxicity/safety assessment. Through this systemic screening program we will get the lead compounds with anti-neuropathic pain activity and preliminary safety, which expect to become the drugs for treating neuropathic pain. This project will promote the development of novel histamine H3 receptor antagonists/inverse agonists as anti-neuropathic pain drugs. It has important scientific significance in medical and neurobiological basic issue about H3 receptor antagonists/inverse agonists in neuropathic analgesia, and would facilitate the progress of interdisciplinary and related talent cultivation.

神经痛对人体危害严重，其诊疗更是世界性难题。现有的神经痛临床用药存在有诸多不足，而相关新药的研发又进展缓慢，因此研发新型神经痛药物具有重大的科学意义和临床价值。组胺H3受体是中枢神经系统中重要的受体，能调控多种神经递质的释放，是当前神经痛镇痛药物研发中最热门的靶点之一。在前期的工作基础上，本项目基于计算机辅助药物设计和药物化学的经典方法，设计、合成全新结构的H3受体拮抗剂/反向激动剂，通过体外活性评价筛选得到高亲和性和高选择性的H3受体拮抗剂/反向激动剂活性分子，再结合经典的体内疼痛模型和神经痛模型以及毒性、安全性评价，最终筛选得到具有神经痛镇痛活性和成药安全性的先导药物分子。本课题将推动新型H3受体拮抗剂/反向激动剂类神经痛药物的发展，对H3受体拮抗剂/反向激动剂作用于神经痛镇痛机制等医学、神经生物学基础问题的研究具有重要的科学意义，并促进交叉学科的发展和相关人才的培养。

神经痛对人体危害严重，其诊疗更是世界性难题。现有的神经痛临床用药存在有诸多不足.，而相关新药的研发又进展缓慢，因此研发新型神经痛药物具有重大的科学意义和临床价值。组胺H3受体是中枢神经系统中重要的受体，能调控多种神经递质的释放，是当前神经痛镇痛药物研发中最热门的靶点之一。本项目基于计算机辅助药物设计和药物化学的经典方法，设计、合成了吡唑[3,4-d]嘧啶-4-酮类组胺H3受体拮抗剂，并通过体外活性评价筛选得到高亲和性和高选择性的H3受体拮抗剂/反向激动剂活性分子，再结合经典的体内疼痛模型和神经痛模型以及毒性、安全性评价，最终筛选得到具有神经痛镇痛活性和成药安全性的先导药物分子Compound 1。此外，本项目还通过PET影像技术对Compound 1进行了药理机制研究。本课题将推动吡唑[3,4-d]嘧啶-4-酮类新型H3受体拮抗剂类神经痛药物的发展，对组胺H3受体拮抗剂作用于神经痛镇痛机制等医学、神经生物学基础问题以及神经分子成像与相关疾病的诊断的研究具有重要的科学意义，并促进交叉学科的发展和相关人才的培养。