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一类全新阿片样二肽的设计合成及镇痛活性研究

ISSN号：0567-7351
期刊名称：《化学学报》
时间：0
分类：Q463[生物学—生理学]
作者机构：[1]兰州大学基础医学院,兰州730000, [2]天津化学化工协同创新中心,天津300072
相关基金：国家自然科学基金（Nos.91213302;21402076）; 中央高校基础研究基金（Nos.lzujbky-2015-168;lzujbky-2015-275）资助

作者：刘鑫[1], 赵龙[1], 王媛[1], 牟凌云[1], 张艺馨[1], 周静静[1], 王锐[1,2]

关键词：阿片肽, 镇痛, 构效关系, 血脑屏障, 非天然氨基酸, opioid peptide, antinociception, structure-activity relationship, blood-brain barrier, unnatural amino acid

中文摘要：

阿片系统是疼痛研究的重要靶点,阿片肽作为一类内源性的神经递质参与诸多生理调节尤其是在痛觉方面的调节,被视为潜在的可以替代吗啡的深层次痛觉调节药物.然而由于其固有的酶解稳定性差、镇痛作用不持久、难以透过血脑屏障等缺陷,从而限制了其在临床方面的应用.我们从阿片肽构效关系的角度出发,设计并合成了4个新型二肽化合物,在多种疼痛模型中显示,中枢系统注射这类化合物能够表现出明显的镇痛活性,外周系统注射发现这类化合物可以通过血脑屏障在中枢神经系统发挥有效的镇痛作用.这一类二肽阿片化合物在多种实验模型中都表现出较好的药理学活性,有可能发展为一类新型具有临床应用潜力的镇痛药物先导化合物.

英文摘要：

The opioid system is one of the most studied pain relieving systems. Opioid peptides have been studied extensively since their discovery, and many efforts have been dedicated to the determination of their intrinsic nature. However, opioid peptides still suffer from serious limitations including lack of oral activity, short duration of action, poor metabolic stability, and relative inability to cross the blood-brain barrier（BBB）. Inspired by the structure-activity studies of opioid peptides, four novel opioid dipeptides were synthesized by introduction of Tyr/Dmt to the N-termius and novel unnatural α-methylene-β-amino acids（Map） to the C-terminus. Their in vitro and in vivo activities were determined and compared. The affinity and selectivity of these dipeptides were evaluated by radioligand binding assay in whole cell preparations from HEK293 cells expressing the μ opioid receptor（MOR） or δ opioid receptor（DOR）, compound 4 exhibited the highest binding affinity toward MOR, and this compound also showed the most significant MOR selectivity over DOR. Pharmacological activities were evaluated in vitro using isolated guinea pig ileum（GPI） for MOR and mouse vas deferens（MVD） for DOR, and the results of GPI and MVD were in accordance with the binding affinity assays. The antinociceptive activities of the compound 4 were assessed in the mouse tail-flick and writhing test after intracerebroventricular（i.c.v.） administration. In the two tests, compound 4 showed good ability to reduce the thermal pain and the inflammatory pain, respectively. Naloxone significantly reversed the activity of the compound, indicating that opioid receptors were involved in its analgesic effects. The compound 4 was then administered inravenously（i.v.） to determine whether this dipeptide was able to cross the BBB. As a result, compound 4 was effective in both tail-flick and writhing test after i.v. administration. Furthermore, the peripherally restricted opioid antagonist naloxone methiodide did not alter the