Synthesis and evaluation of novel 2,3-dihydrobenzo[b][1,4]dioxin- and indolealkylamine derivatives as potential antidepressants

Article abstract of DOI:10.1002/ardp.201300238

A series of 2,3-dihydrobenzo[b][1,4]dioxin- and indolealkylamine derivatives were synthesized and the target compounds were evaluated for their binding affinities at the 5-HT_1A receptor and serotonin transporter. Antidepressant-like activities of the compounds were screened using the tail suspension and forced swim tests in mice. Preliminary results indicated that the target compounds exhibited high binding affinities at the 5-HT_1A receptor and serotonin transporter, and produced marked antidepressant-like effects. The best example from this study, compound 5, exhibited high binding affinities for the 5-HT_1A receptor (K_i = 96 nM) and serotonin transporter (K_i = 9.8 nM). The intrinsic activity of compound 5 showed agonistic property to the 5-HT_1A receptor and inhibition of the 5-HT transporter. Furthermore, compound 5 exhibited greater antidepressant efficacy than fluoxetine and showed acceptable pharmacokinetic properties. A series of 3-(2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-3-yl)methyl) piperazin-1-yl)ethyl-1H-indole derivatives were synthesized and the target compounds were evaluated for their antidepressant activities in vitro and in vivo. The compounds described were also evaluated for dual 5-HTT and 5-HT _1A receptor activities.