Design, Synthesis and Biological Evaluation of Novel Histamine H3 Receptor Antagonists as Potential Analgesic
作者单位：Department of PharmacyRenmin Hospital of Wuhan University
会议名称：《2016年中国药学大会暨第十六届中国药师周》
会议日期：2016年
学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学]
基 金：国家自然科学基金—青年科学基金项目(81602946)
关 键 词：histamine H3 receptor benzofuran derivatives anti-nociception
摘 要：Histamine H3 receptor（H3 R） is a potential target in the treatment of various central nervous system（CNS） diseases, metabolic disorders and pain. In the absence of crystal structure of H3 receptor, a ligand-based approach was took in this work. A 3 D-QSAR pharmacophore model was generated based on a set of known structurally diverse H3 R antagonists/inverse agonists, and its qualities were evaluated by cost function. The predictive power was validated by test set prediction and Fischer`s randomization test. On the basis of the pharmacophore model, a series of benzofuran derivatives were synthesized. The most promising compound, ethyl 2-methyl-5-（3-（3-methylpiperidin-1-yl）propoxy）benzofuran-3-carboxylate（1） showed high affinity for H3 receptor and exhibited dose-dependent anti-nociceptive effects in mice formalin model. In summary, compound 1 may facilitate the development of a novel class of drugs for the treatment of pain.