芳基、芳甲基及哌嗪基脒类化合物的设计与合成及5-HT和NE重摄取双重抑制活性

Design,Synthesis and 5-HT/NE Dual Reuptake Inhibition Activity of Phenylbenzamidine Derivatives

基于药效团模型和前期的研究结果,设计合成了一类全新结构类型的芳基、芳甲基及哌嗪基脒类化合物,通过1HNMR,HRMS对化合物结构进行了确证,并完成了初步的体外药理活性评价.结果表明,这些化合物均显示出不同程度的5-HT和NE重摄取抑制活性,其中化合物4b的活性最好,化合物4a和8a在整体动物抗抑郁药效学实验中表现出明确的抗抑郁活性.

Depression is a kind of common and severe mental illness. Over the past few years, a number of studies have emerged suggesting that treatment with antidepressants which simultaneously enhance both noradrenergic as well as serotonergie neurotransmission including Venlafaxine and Duloxetine may result in higher response or remission rates than treatment with antidepressants which selectively enhance serotonergic neurotransmission. Based on the pharmacophore information and the analysis of structure-activity relationship of SSRIs and SNRIs, a series of substituted phenylbenzamidine derivatives were designed and synthesized in order to search for lead compounds with dual activity. All of them were new compounds, and their structures were confirmed by ^1H NMR and HRMS. Preliminary in vitro pharmacological tests show that all target compounds exhibit 5-HT reuptake inhibition activity and some compounds exhibit NE reuptake inhibition activity. Among the tested, compounds 4b exhibit potent inhibitory activity against 5-HT and NE reuptake in vitro. Compounds 4a and 8a exhibit potent antidepressant activity in vivo. These phenylbenzamidine designed can be further optimized for finding more potent 5-HT/NE dual reuptake inhibitors and antidepressant candidates as well.