Structural basis for pharmacotherapeutic action of triple reuptake inhibitors

Most first-line pharmacotherapeutic strategies for depression aim to boost serotonin and norepinephrine levels. However, 35% of patients with depression do not respond adequately to these treatments or experience adverse side effects. The serotonin–norepinephrine–dopamine reuptake inhibitors, also known as triple reuptake inhibitors (TRIs), are emerging as promising antidepressants with greater potency and fewer side effects. Here, we determine an ensemble of structures of DAT in complex with five distinct TRIs. Tesofensine and dasotraline stabilize DAT in an outward-facing conformation, while centanafadine, ansofaxine, and nefazodone capture the inward-facing conformation. These structures reveal binding poses and interactions involved in the association of inhibitors. Notably, ansofaxine binds at a location which is much closer to the intracellular membrane surface. Through extensive structural analysis, we establish a comprehensive blueprint for the association of these TRIs, which is crucial for future drug development aimed at achieving potent antidepressant with fewer side effect. Most current antidepressants target SERT and NET but often have limited efficacy or side effects. Here, authors reveal how five triple reuptake inhibitors bind to DAT, offering structural insights to guide development of more effective antidepressants.