Synthesis and structure-activity relationship of di-(3,8-diazabicyclo[3.2.1]octane) diquaternary ammonium salts as unique analgesics

被引：8

作者：

Liu, H ^{[1
]}

Cheng, TM ^{[1
]}

Zhang, HM ^{[1
]}

Li, RT ^{[1
]}

机构：

[1] Peking Univ, Sch Pharmaceut Sci, Beijing 100083, Peoples R China

来源：

ARCHIV DER PHARMAZIE | 2003年 / 336卷 / 11期

关键词：

di-(3,8-diazabicyclo[3.2.1]octane) diquaternary ammonium salts; analgesic activities; structure-activity relationship;

D O I：

10.1002/ardp.200300749

中图分类号：

R914 [药物化学];

学科分类号：

100701 [药物化学];

摘要：

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 3a-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.

引用

页码：510 / 513

页数：4

共 10 条

[1]

Mono- and disubstituted-3,8-diazabicyclo[3.2.1]octane derivatives as analgesics structurally related to epibatidine: Synthesis, activity, and modeling [J].