title: 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 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.
authors: 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.
authors: Jeffery N
authors: JN
authors: Talbot
authors: Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, USA.
authors: Laura M
authors: LM
authors: Geffert
authors: Research Center on Substance Abuse and Depression, College of Pharmacy, Roseman University of Health Sciences, 11 Sunset Way, Henderson, NV 89014, USA.
authors: Jessica E
authors: JE
authors: Jorvig
authors: Research Center on Substance Abuse and Depression, College of Pharmacy, Roseman University of Health Sciences, 11 Sunset Way, Henderson, NV 89014, USA.
authors: Ruben I
authors: RI
authors: Goldstein
authors: Department of Basic Sciences, Touro University Nevada, 874 American Pacific Dr., Henderson, NV 89014, USA.
authors: Cienna L
authors: CL
authors: Nielsen
authors: Raabe College of Pharmacy, Ohio Northern University, 525 S. Main St., Ada, OH 45810, USA.
authors: Nicholas E
authors: NE
authors: Wolters
authors: Raabe College of Pharmacy, Ohio Northern University, 525 S. Main St., Ada, OH 45810, USA.
authors: Mary Ellen
authors: ME
authors: Amos
authors: Raabe College of Pharmacy, Ohio Northern University, 525 S. Main St., Ada, OH 45810, USA.
authors: Caitlin A
authors: CA
authors: Munro
authors: Raabe College of Pharmacy, Ohio Northern University, 525 S. Main St., Ada, OH 45810, USA.
authors: Elizabeth
authors: E
authors: Dallman
authors: Psychobiology Section, National Institute on Drug Abuse, Intramural Research Program, NIH, Baltimore, MD 21224, USA.
authors: Maddalena
authors: M
authors: Mereu
authors: Psychobiology Section, National Institute on Drug Abuse, Intramural Research Program, NIH, Baltimore, MD 21224, USA.
authors: Gianluigi
authors: G
authors: Tanda
authors: Psychobiology Section, National Institute on Drug Abuse, Intramural Research Program, NIH, Baltimore, MD 21224, USA.
authors: Jonathan L
authors: JL
authors: Katz
authors: Phusis Therapeutics, Inc., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors: Martín
authors: M
authors: Indarte
authors: Departments of Chemistry and Biochemistry, Center for Computational Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, USA.
authors: Jeffry D
authors: JD
authors: Madura
authors: Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, USA.
authors: Hailey
authors: H
authors: Choi
authors: Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, USA.
authors: Rehana K
authors: RK
authors: Leak
authors: Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, USA. Electronic address: surratt@duq.edu.
authors: Christopher K
authors: CK
authors: Surratt
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D003198:Computer Simulation; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008810:Mice, Inbred C57BL; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010636:Phenols / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
chemical_list: D000928:Antidepressive Agents; D018765:Dopamine Uptake Inhibitors; D016202:N-Methylaspartate; D018696:Neuroprotective Agents; D010636:Phenols; D010880:Piperidines; D017367:Selective Serotonin Reuptake Inhibitors; C109643:Ro 25-6981
keywords: Antidepressant; Ketamine; Monoamine transporter; Ro-25-6981; Serotonin selective reuptake inhibitor; Virtual screen