关键词: 5-羟色胺, 去甲肾上腺素, 药效团模型, 双重重摄取抑制剂

Abstract:

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 serotonergic 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.

Key words: Serotonin, Norepinephrine, Pharmacophore model, Dual reuptake inhibitors