(-)-Syringaresinol Exerts an Antidepressant-like Activity in Mice by Noncompetitive Inhibition of the Serotonin...

Albizia julibrissin Durazz. is one of the most popular herbs used for depression treatment, but the molecular basis for its mechanism of action has not been fully addressed. Previously, we isolated and identified two lignan glycoside derivatives that were shown to noncompetitively inhibit serotonin transporter (SERT) activity but with a relatively low inhibitory potency compared with those of conventional antidepressants.

We characterized the pharmacological profile of the parental compound of these previously isolated lignan glycosides, (-)-syringaresinol (SYR), in inhibiting SERT by using biochemical, pharmacological, and behavioral approaches.

SYR, as a potent inhibitor, decreases SERT V_max but with little change in K_m for its fluorescent substrate. SYR was shown to block the conformational conversion essential for substrate transport by stabilizing SERT in an outward-open and inward-closed conformation. In addition, our molecular docking and biochemical validation demonstrated that SYR binds to an allosteric site in SERT and noncompetitively inhibits SERT transport and binding activity. Furthermore, administration of SYR was indicated to exert an antidepressant-like activity and to effectively attenuate chronic unpredictable mild stress (CUMS)-induced abnormalities in behaviors and synaptic protein expression in depressive animal models.

This study not only provides molecular insights into the mechanism of action of A. julibrissin in the treatment of depression, but also opens up the possibility of development of a novel class of allosteric site-targeted therapeutic agents with an underlying mechanism of action different from that of conventional antidepressants.