Design and Synthesis of Arylamidine Derivatives as Serotonin/Norepinephrine Dual Reuptake Inhibitors

Abstract

To improve the in vivo antidepressant activity of previously reported serotonin (5-HT) and norepinephrine (NE) dual reuptake inhibitors, three series of arylamidine derivatives were designed and synthesized. The in vitro 5-HT and NE reuptake inhibitory activities of these compounds were evaluated, and compound II-5 was identified as the most potent 5-HT (IC50 = 620 nM) and NE (IC50 = 10 nM) dual reuptake inhibitor. Compound II-5 exhibited potent antidepressant activity in the rat tail suspension test and showed an acceptable safety profile in a preliminary acute toxicity test in mice. Our results show that these arylamidine derivatives exhibit potent 5-HT/NE dual reuptake inhibition and should be explored further as antidepressant drug candidates.

Design Strategies, Chemistry and Therapeutic Insights of Multi-target Directed Ligands as Antidepressant Agents

“…Based on the previous studies [ 167 ] and in a quest to discover potential lead(s) for antidepressant-like activity, Wen et al . designed and synthesized a series of arylamidine derivatives (Fig.…”

“…Acute toxicity studies were performed at the dose of 200 and 400 mg/kg after 20h and results demonstrated that compound 72a exhibited low toxicity with LD 50 value >400 mg/kg. SAR studies suggested that the substitution with electron-withdrawing groups at the phenyl ring increased the binding affinities, whereas that of electron-donating groups decreased the affinities [ 167 ].…”

Piperazine, a Key Substructure for Antidepressants: Its Role in Developments and Structure‐Activity Relationships

“…Wen et al. designed and synthesized three series of piperazine bearing arylamidine derivatives to improve antidepressant activity earlier reported 5‐HT receptors ligands [103] . Initially, synthesized compounds were screened for in vitro serotonin (5‐HT) and norepinephrine (NE) reuptake inhibitory activity.…”