Li Ang, Wang Xin, Yue Cai-Qin, Ye Jia, Li Chang-Ling, Li Run-Tao
Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100083, PR China.
Bioorg Med Chem Lett. 2007 Sep 15;17(18):5078-81. doi: 10.1016/j.bmcl.2007.07.010. Epub 2007 Jul 13.
In order to improve the analgesic activity of lead compound 7a, two series of dispirocyclopiperazinium (DSPZ) salts 9a-h, 10a-e and compounds 14, 15 were synthesized and evaluated for their in vivo analgesic activity both by acetic acid induced writhing test and hot plate test. Compounds 9h, 14, and 15 exhibited better analgesic activities than 7a. Several important structure-activity relationships were revealed from this study: (1) the introduction of aryl group would obviously improve the activity; (2) it was favorable to enhance the analgesic activity and reduce the toxicity to incorporate alkyl group with suitable length in the molecule; (3) carbamate analogues displayed lower toxicity than carboxylic ester analogues; (4) hydroxylation and chlorination of lead compound could increase the analgesic activity in hot plate test.
为了提高先导化合物7a的镇痛活性，合成了两个系列的双螺环哌嗪鎓（DSPZ）盐9a - h、10a - e以及化合物14、15，并通过醋酸诱导扭体试验和热板试验对它们的体内镇痛活性进行了评价。化合物9h、14和15表现出比7a更好的镇痛活性。该研究揭示了几个重要的构效关系：（1）引入芳基会明显提高活性；（2）在分子中引入长度合适的烷基有利于增强镇痛活性并降低毒性；（3）氨基甲酸酯类似物的毒性低于羧酸酯类似物；（4）先导化合物的羟基化和氯化可提高热板试验中的镇痛活性。
