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

DOI

10.1016/j.pbb.2016.08.007

Jeffery N. Talbot, Research Center on Substance Abuse and Depression, College of Pharmacy, Roseman University of Health Sciences, 11 Sunset Way, Henderson, NV 89014, USA. Electronic address: jtalbot@roseman.edu.
Laura M. Geffert, Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, USA.
Jessica E. Jorvig, Research Center on Substance Abuse and Depression, College of Pharmacy, Roseman University of Health Sciences, 11 Sunset Way, Henderson, NV 89014, USA.
Ruben I. Goldstein, Research Center on Substance Abuse and Depression, College of Pharmacy, Roseman University of Health Sciences, 11 Sunset Way, Henderson, NV 89014, USA.
Cienna L. Nielsen, Department of Basic Sciences, Touro University Nevada, 874 American Pacific Dr., Henderson, NV 89014, USA.
Nicholas E. Wolters, Raabe College of Pharmacy, Ohio Northern University, 525 S. Main St., Ada, OH 45810, USA.
Mary Ellen Amos, Raabe College of Pharmacy, Ohio Northern University, 525 S. Main St., Ada, OH 45810, USA.
Caitlin A. Munro, Raabe College of Pharmacy, Ohio Northern University, 525 S. Main St., Ada, OH 45810, USA.
Elizabeth Dallman, Raabe College of Pharmacy, Ohio Northern University, 525 S. Main St., Ada, OH 45810, USA.
Maddalena Mereu, Psychobiology Section, National Institute on Drug Abuse, Intramural Research Program, NIH, Baltimore, MD 21224, USA.
Gianluigi Tanda, Psychobiology Section, National Institute on Drug Abuse, Intramural Research Program, NIH, Baltimore, MD 21224, USA.
Jonathan L. Katz, Psychobiology Section, National Institute on Drug Abuse, Intramural Research Program, NIH, Baltimore, MD 21224, USA.
Martín Indarte, Phusis Therapeutics, Inc., 3210 Merryfield Row, San Diego, CA 92121, USA.
Jeffry D. Madura, Departments of Chemistry and Biochemistry, Center for Computational Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, USA.
Hailey Choi, Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, USA.
Rehana K. Leak, Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, USA.
Christopher K. Surratt, Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, USA. Electronic address: surratt@duq.edu.

Document Type

Journal Article

Publication Date

11-1-2016

Publication Title

Pharmacology, biochemistry, and behavior

Volume

150-151

First Page

22

Last Page

30

Keywords

Antidepressant, Ketamine, Monoamine transporter, Ro-25-6981, Serotonin selective reuptake inhibitor, Virtual screen

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 requires chronic treatment to produce antidepressant-like effects. MI-4 (10mg/kg, bid) produced rapid (three-day) antidepressant-like effects in the social avoidance test following 10days of social defeat stress. Unlike ketamine, chronic administration of MI-4 increased social interaction scores while improving resiliency to the mood-altering effects of stress to over 70%. Importantly, MI-4 exhibited minimal abuse liability in behavioral and neurological models (conditioned place preference and dopamine in vivo microdialysis). MI-4 was found to be Ro-25-6981, an ifenprodil analog and reputed NMDA antagonist. The data suggest that Ro-25-6981, previously known for rapid-acting glutamatergic antidepressant actions, may also functionally inhibit monoamine reuptake and produces sustained antidepressant effects in vivo. This demonstrates, as proof of principle, the viability of combining these mechanisms to produce rapid and sustained antidepressant-like effects. Overall, these findings suggest MAT computational model-based virtual screening is a viable method for identifying antidepressant lead compounds of unique scaffold.

Open Access

OA

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