摘要
目的 研究通过高通量筛选与体内试验相结合寻找抗抑郁新药先导化合物的技术方法。方法 采用高通量筛选方法在 5 0 0 0多种化合物中筛选具有 5 HT重摄取抑制作用的活性化合物 ,然后应用行为绝望抑郁模型———小鼠游泳试验和小鼠悬尾试验探讨活性化合物J0 1113 ,J0 1114和J10 745的抗抑郁作用。结果 体外试验表明 ,5 0 0 0多种化合物经高通量筛选后 ,J0 1113 ,J0 1114和J10 745均显示较强的 5 HT重摄取抑制活性。J0 1113 ,J0 1114和J10 745的IC50 分别为 1.3 0 4× 10 -10 ,9.0 3 6× 10 -10 ,1.44 7× 10 -7mol·L-1。小鼠悬尾试验结果显示J0 1113连续给药 3d或 5d能明显减少悬尾小鼠的静止时间[( 70± 5 0 )s,( 10 0± 5 0 )s],同模型小鼠 [( 10 0± 3 0 )s ,( 170± 40 )s]相比差异极显著 (P <0 .0 5 ,P <0 .0 1)。小鼠游泳试验结果表明 ,J0 1113组小鼠连续给药 3d或 5d静止时间为 [( 10± 16)s ,( 19± 2 5 )s]也显著低于模型对照组 [( 60± 40 )s,( 5 0± 3 0 )s],两者相比差异极显著 (P <0 .0 1,P <0 .0 5 )。在这两种模型中J0 1114,J10 745与对照组比静止时间虽有减少趋势 ,但均无显著性差异 (P >0 .0 5 )。结论 结果提示应用高通量筛选体系 ,可实现大规模高效率抗抑郁药先导化合物的发现 ,
OBJECTIVE: To establish a screening method for finding new antidepressant leading compounds and evaluate the active compounds in vitro and in vivo. METHODS: The effects of more than 5000 compounds on 5-HT reuptake were tested by high throughput screening (HTS) in vitro. Three active compounds, J01113, J01114 and J10745 were selected to test their antidepressant effects by mouse forced swimming and the tail suspension tests. RESULTS: The results obtained by HTS in vitro revealed that J01113, J01114 and J10745 could strongly inhibit 5-HT reuptake. The IC50 of J01113, J01114 and J10745 were 1.304 × 10-10, 9.036 × 10-10 and 1.447 × 10-7 mol·L-1 respectively. After administration for 3 and 5 days, J01113 (30 mg·kg-1) p.o. could significantly reduce the immobility time compared with control [(70±50)s vs (100±30)s, (100±50)s vs (170±40)s, P<0.05, P< 0.01] in the tail suspension test and reduced the immobility compared with control [(10±16)s vs (60±40)s, (19±25)s vs (50± 30)s, P < 0.01, P < 0.05] in mouse forced swimming test, respectively. There were no markedly effects of J01114 and J10745 in both tests in vivo. CONCLUSION: These results indicated that the high throughput screening method could efficiently find antidepressant leading compounds. J01113 may be a potential antidepressant drug.
出处
《中国药学杂志》
EI
CAS
CSCD
北大核心
2003年第4期263-266,共4页
Chinese Pharmaceutical Journal
基金
国家高技术研究发展计划 ( 863)项目 ( 2 0 0 1AA2 34 0 2 1)
国家自然科学基金 ( 30 17114 8)
