Study summary · research use only
Structural basis for pharmacotherapeutic action of triple reuptake inhibitors
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This structural study (species not specified for the source protein; a dopamine transporter, DAT, in complex with inhibitors) determined an ensemble of structures of DAT bound to five distinct triple reuptake inhibitors (TRIs): tesofensine, dasotraline, centanafadine, ansofaxine, and nefazodone. Tesofensine and dasotraline stabilized DAT in an outward-facing conformation, while centanafadine, ansofaxine, and nefazodone captured an inward-facing conformation; ansofaxine bound at a site closer to the intracellular membrane surface than the others. The authors report that these structures reveal binding poses and interactions for these inhibitors, intended to inform future drug development targeting fewer side effects.
Abstract
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.
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