Zhao Ming, Li Zheng, Peng Li, Tang Yu-Rong, Wang Chao, Zhang Ziding, Peng Shiqi
College of Pharmaceutical Sciences, Capital Medical University, Beijing 100054, PR China.
Bioorg Med Chem. 2007 Apr 15;15(8):2815-26. doi: 10.1016/j.bmc.2007.02.023. Epub 2007 Feb 15.
Based on the knowledge that imidazoline can result in analgesic action due to its selective binding with the prostacyclin receptor, 20 1-oxyl-2-substitutedphenyl-4,4,5,5-tetramethylimidazolines (3a-t) were prepared in moderate yields. At 0.13 mmol/kg dose, their in vivo analgesic activities were evaluated after the mice were administered at 30, 60, 90, and 150 min. Compared with the pain threshold (12.27+/-9.56-17.71+/-7.00%) of normal saline (NS) receiving mice, the pain threshold (23.42+/-8.14% to 102.58+/-10.66%) of 3a-t receiving mice increases significantly. Considering a prostacyclin receptor targeting analgesic agent usually had bleeding action and to appraise the bleeding risk, the in vivo tail bleeding time of 1.30 mmol/kg 3a-t receiving mice was found to be ranged from 116.3+/-8.2s to 120.3+/-9.2s, which was substantially equal to that (117.8+/-8.4s to 119.0+/-8.6s) of NS receiving mice. Based on the possibility of imidazoline acting as vasodilator, the in vitro vasorelaxations of 3a-t were tested using the rat aortic strip model. When the aortic strip contracted by noradrenaline (NE, final concentration 10(-7)mol/l) was treated with 3a-t (final concentration 5 x 10(-4)mol/l), only lower percentage inhibitions (6.55+/-5.70-37.40+/-4.07%) were recorded, implying that the vasorelaxation of 3a-t was neglectable. By selecting appropriate molecular descriptors generated from e-dragon server, the QSAR model of the analgesic activities of 3a-t was constructed using the multiple linear regression method. The established QSAR model showed reasonable accuracy and thus it is promising to be used for screening new 1-oxyl-2-substitutedphenyl-4,4,5,5-tetramethylimidazoline derivatives as analgesic agents.
基于咪唑啉因其与前列环素受体的选择性结合而能产生镇痛作用这一认识，制备了20种1 - 氧基 - 2 - 取代苯基 - 4,4,5,5 - 四甲基咪唑啉（3a - t），产率适中。在0.13 mmol/kg剂量下，在给小鼠给药30、60、90和150分钟后评估其体内镇痛活性。与接受生理盐水（NS）的小鼠的痛阈（12.27±9.56 - 17.71±7.00%）相比，接受3a - t的小鼠的痛阈（23.42±8.14%至102.58±10.66%）显著提高。考虑到靶向前列环素受体的镇痛剂通常具有出血作用，为评估出血风险，发现接受1.30 mmol/kg 3a - t的小鼠的体内尾部出血时间为116.3±8.2秒至120.3±9.2秒，这与接受NS的小鼠的出血时间（117.8±8.4秒至119.0±8.6秒）基本相等。基于咪唑啉作为血管扩张剂的可能性，使用大鼠主动脉条模型测试了3a - t的体外血管舒张作用。当用3a - t（终浓度5×10⁻⁴mol/l）处理由去甲肾上腺素（NE，终浓度10⁻⁷mol/l）收缩的主动脉条时，仅记录到较低百分比的抑制率（6.55±5.70 - 37.40±4.07%），这意味着3a - t的血管舒张作用可忽略不计。通过选择从电子龙服务器生成的合适分子描述符，使用多元线性回归方法构建了3a - t镇痛活性的QSAR模型。所建立的QSAR模型显示出合理的准确性，因此有望用于筛选新的1 - 氧基 - 2 - 取代苯基 - 4,4,5,5 - 四甲基咪唑啉衍生物作为镇痛剂。
