A novel triple reuptake inhibitor with rapid antidepressant properties identified by virtual screening (1144.1)

Abstract

A continuing challenge in treating depression is therapeutic delay and resistance to available treatments. Hence, the growing interest in developing antidepressants (AD) with rapid onset (hours to days) and novel mechanisms of action. For example, the glutamatergic antagonist ketamine has rapid AD efficacy but is limited by poor bioavailability, short duration of effect, and potential for abuse. Here we report MI‐4, identified through virtual screening targeting the human dopamine transporter, inhibited the human monoamine transporters of dopamine (DA), norepinephrine (NE), and serotonin (5‐HT) in vitro. In vivo administration of MI‐4 in mice induced robust, dose‐dependent AD‐like behaviors in acute models of learned helplessness (tail suspension test and forced swim test). Moreover, 21‐day administration of MI‐4 reduced drinking latency times comparable to fluoxetine in the novelty‐induced hypophagia test, which requires chronic treatment to produce AD effects. Interestingly, like ketamine, MI‐4 also exhibits NMDA receptor antagonism and produced rapid (3‐day) and chronic (21‐day) AD‐like effects in the social avoidance test following 10 days of social defeat, by increasing social interaction scores 2‐fold vs. vehicle controls while improving resiliency to near 70%. Unlike ketamine, MI‐4 exhibited minimal abuse liability in behavioral and neurological models (conditioned place preference and DA in vivo microdialysis). These data suggest MI‐4 is a novel, multiple mechanism antidepressant with rapid and chronic properties.