摘要
目的采用地塞米松建立斑马鱼骨质疏松模型，筛选先导物G39及其结构类似物的抗骨质疏松活性。方法斑马鱼 AB 系胚胎受精后6~72 h 浸于地塞米松溶液建模，受精后3 d分组给药直至受精后6 d，收集固定斑马鱼幼体；采用茜素红染色法显示成骨发育状况，显微拍照后以 G39为对照，进行斑马鱼头面骨成骨面积和骨矿化密度的半定量分析，比较六种2-乙酰苯并五元杂环类化合物潜在的抗骨质疏松活性。结果 G395μg/ml 组对地塞米松导致的斑马鱼骨质疏松具有显著的改善作用，且实验结果与地塞米松大鼠模型具有一致性。以此筛选 G39衍生物体内活性，发现苯并呋喃衍生物410活性优于 G39。结论地塞米松斑马鱼骨质疏松模型评价周期缩短、成本低，使抗骨质疏松药物体内活性批量筛选成为可能，为更快更准地发现抗骨质疏松候选药物打下坚实基础。通过本研究筛选得到了全新结构类型的抗骨质疏松化合物410，其活性较 G39更强，值得进一步研究。
Objective To screen the anti-osteoporosis activities of lead compound G39 and its structural analogues using dexamethasone 6-72 hpf zebrafish model. Methods In groups, embryos from AB lines of 6 hpf zebrafish were incubated in dexamethasone solution for 72 h and drugs were then administered, respectively. Embryos were cultured till 6 dpf and then harvested followed by alizarin red staining, rehydration, decoloration, photomicrography, and analysis of staining results. Anti-osteoporosis activity screening experiments were carried out through the above steps in this dexamethasone zebrafish model. The experiments were divided into groups including wild type control, model control, model solvent control, and drug evaluation groups with various doses. Results The 5μg/ml G39 group showed significant activity in this dexamethasone zebrafish model, which is consistent with resultsnbsp;from glucocorticoid rats model. Parallel screening of G39 derivatives was performed and it was discovered that benzofuran derivative 410 showed greater activity than G39 did. 〈 Conclusion Due to its shortened evaluation cycle and low cost, dexamethasone zebrafish model makes it possible to evaluate the activities of anti-osteoporosis drugs in large quantities in vivo, laying a solid foundation for the faster and more accurate discovery of anti-osteoporosis drugs. An anti-osteoporosis compound 410, which shows a whole new structure and a greater activity than G39 does, is screened out through this study, and is worthy of further investigation.
出处
《中国医药生物技术》
2015年第3期211-217,共7页
Chinese Medicinal Biotechnology
基金
国家自然科学基金(81473097)
