Design, Synthesis, and Structure-Activity Relationship Studies of Novel Indolyalkylpiperazine Derivatives as Selective 5-HT Receptor Agonists.

5-HT receptor (5-HTR) agonists have been implicated in the treatment of a variety of central nervous system (CNS) diseases such as depression and anxiety, et al. Based on our previously found compound ( = 51 ± 16 nM) obtained by virtual screening, a series of derivatives were designed and synthesized by the modification of the amide tail group as well as indole headgroup of . SAR exploration found that amide tail group and indole headgroup play pivotal roles in determining the binding affinity and selectivity on dopamine and serotonin receptor subtypes. Among all tested compounds, has a value of 5 ± 0.6 nM with a good selectivity toward 5-HTR. The [S] GTPγS assay showed that is a full agonist toward 5-HTR with an EC value of 0.059 nM, which shows 266.2 and 146.4-fold selectivity to 5-HT and D respectively. Molecular dynamics simulations and molecular docking studies with 5-HTR- were performed to disclose the mechanism of its high activity and selectivity. Finally, a detailed stepwise induced signal transduction mechanism of 5-HTR is proposed.