Docking over 200 million small molecules against the inward-open state of the serotonin transporter (SERT) identified two potent, low-nanomolar inhibitors that stabilize an outward-closed conformation. These compounds showed little activity against common off-targets, and a cryo-EM structure confirmed the predicted binding geometry. In mouse behavioral assays, both compounds exhibited anxiolytic- and anti-depressant-like activity, with potencies up to 200-fold greater than fluoxetine (Prozac), and one substantially reversed morphine withdrawal effects. The work suggests a promising path toward new treatments for depression, anxiety, and addiction with improved safety.
A systematic review of 91 fMRI studies on acute psychedelic effects found substantial methodological heterogeneity. Only 51 unique samples were used across the 91 papers, and 54% of studies did not meet current standards for correcting Type I errors or controlling motion artifacts. Psilocybin and LSD consistently modulated connectivity along the sensorimotor-association cortical axis. Ketamine consistently increased activation in the dorsomedial prefrontal cortex. The review calls for future adoption of pre-registration, standardized processing and statistical testing, and data sharing to improve rigor.
The serotonin transporter (SERT) adopts three conformations, and most antidepressants target its outward-open state. Ibogaine, which targets the inward-open state, has an unusual antidepressant profile but is cardiotoxic. Computational docking of over 200 million small molecules against the ibogaine-stabilized inward-open SERT identified 36 top compounds; 13 inhibited SERT with potencies from 29 to 5000 nM. Optimization yielded two inhibitors with Ki values as low as 3 nM that stabilized an outward-closed state and showed little off-target activity. A cryo-EM structure confirmed the predicted binding geometry. In mice, both compounds showed anxiolytic and antidepressant activity with potencies up to 200 times greater than fluoxetine.