Rapid and sustained antidepressant properties of an NMDA antagonist/monoamine reuptake inhibitor identified via transporter-based virtual screening.

ABSTRACT: Rational design of lead compounds targeting monoamine transporters (MATs) is critical to developing novel therapeutics to treat psychiatric disorders including depression and substance abuse. A 3-D dopamine transporter (DAT) computer model was used to virtually screen a commercially available small molecule library for high DAT affinity drug-like compounds. One hit, coded "MI-4", inhibited human dopamine, norepinephrine, and serotonin transporters in vitro. In vivo administration in mice induced robust, dose-dependent antidepressant-like behaviors in learned helplessness models (tail suspension and forced swim tests). Moreover, chronic administration (21day, 10mg/kg, bid) reduced drinking latencies comparable to fluoxetine (10mg/kg, bid) in the novelty-induced hypophagia test, which requir

SUBMITTER: Talbot JN 

PROVIDER: S-EPMC9575003 | biostudies-literature | 2016 Nov - Dec

REPOSITORIES: biostudies-literature