The serotonin transporter (SERT) transports serotonin back to the presynaptic neuron to terminate serotonergic neurotransmission. SERT is the primary target for several antidepressants, e.g., S-citalopram and imipramine, to alleviate depression symptoms. A crystal structure of SERT reveals that two S-citalopram molecules are bound in the central binding (S1) site and the extracellular vestibule (S2 site). Our combined in vitro and in silico analysis indicates that the bound S-citalopram or imipramine in S1 can allosterically modulate the ligand binding to S2 through altering protein conformations. Remarkably, Lu AF60097, the first high-affinity S2-bound SERT inhibitor, allosterically couples the ligand binding to S1 through a similar mechanism. The SERT inhibition by Lu AF60097 is demonstrated by the potentiated imipramine binding and increased rat hippocampal serotonin level. These understandings of the S1-S2 coupling mechanism facilitate the rational design and discovery of even higher-affinity SERT allosteric inhibitors, which will lead towards practical therapeutic interventions on depression with allosteric modulations.

Towards discovering higher-affinity allosteric inhibitors of the serotonin transporter for practical therapeutic interventions on depression

ACS Fall 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.