Liu Hong, Cheng Tie-Ming, Zhang Hong-Mei, Li Run-Tao
School of Pharmaceutical Sciences, Peking University, Beijing, P. R. China.
Arch Pharm (Weinheim). 2003 Nov;336(11):510-3. doi: 10.1002/ardp.200300749.
Based on the structure characteristics of the lead compounds, 1, 1' octanedioyl-4, 4'-dimethyl-4, 4'-dibenzyl dipiperazinium dibromide (2) and 3, 8-disubstituted-3, 8-diazabicyclo [3.2.1]octanes (DBO), di-(3, 8-diazabicyclo [3.2.1]octane) diquaternary ammonium salts 3 a-c were designed and synthesized through a highly practical procedure. Target compounds 3 a-c and the hydrochloride salts of their precursors 10 a-c were evaluated for their in vivo analgesic and sedative activities. Interestingly, the introduction of an endoethylenic bridge in the piperazine of lead compound 2 causes loss of the analgesic activity and increases the toxicity dramatically. This result shows that the flexible conformation of piperazine in compound 2 is favorable for interaction with the receptor, and the quaternization of compounds 10 a-c is the main reason for the toxicity increase.
基于先导化合物的结构特征，通过高度实用的方法设计并合成了1,1'-辛二酰基-4,4'-二甲基-4,4'-二苄基二哌嗪二溴化物(2)和3,8-二取代-3,8-二氮杂双环[3.2.1]辛烷(DBO)、二-(3,8-二氮杂双环[3.2.1]辛烷)二季铵盐3a-c。对目标化合物3a-c及其前体10a-c的盐酸盐进行了体内镇痛和镇静活性评价。有趣的是，在先导化合物2的哌嗪中引入内亚乙基桥会导致镇痛活性丧失，并显著增加毒性。该结果表明化合物2中哌嗪的柔性构象有利于与受体相互作用，而化合物10a-c的季铵化是毒性增加的主要原因。
