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Nathan HegerFollow

Description

The small molecule ketamine has generated much interest due to its rapid antidepressant effects. Despite having a rapid onset, ketamine has poor bioavailability, short duration of action, toxicities with long-term use, and a high potential for abuse. The molecule MI-4 (RO 25-6981) has also been shown to have both a rapid and sustained antidepressant effect. Most of the research into the mechanism of the rapid onset of MI-4 and ketamine has focused on their interaction with the NMDA receptor in addition to some monoamine transporters. Some recent publications have shown a significant role of AMPA receptors in the ketamine antidepressant response. Inhibiting the feedback signaling pathway for the AMPA receptors blocked ketamine activity. The hypothesis is that ketamine or ketamine metabolites appear to function as AMPA potentiators. These experiments will allow us to further understand the mechanism of action of MI-4 and how the modifications to the molecule may affect inhibition activity.

Disciplines

Biochemistry | Laboratory and Basic Science Research | Medical Pharmacology | Medicinal Chemistry and Pharmaceutics | Molecular Biology | Pharmacology

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Efforts to increase the ketamine-like activity of the rapid-acting antidepressant RO-25-6981 (MI-4) by increasing AMPA potentiation

The small molecule ketamine has generated much interest due to its rapid antidepressant effects. Despite having a rapid onset, ketamine has poor bioavailability, short duration of action, toxicities with long-term use, and a high potential for abuse. The molecule MI-4 (RO 25-6981) has also been shown to have both a rapid and sustained antidepressant effect. Most of the research into the mechanism of the rapid onset of MI-4 and ketamine has focused on their interaction with the NMDA receptor in addition to some monoamine transporters. Some recent publications have shown a significant role of AMPA receptors in the ketamine antidepressant response. Inhibiting the feedback signaling pathway for the AMPA receptors blocked ketamine activity. The hypothesis is that ketamine or ketamine metabolites appear to function as AMPA potentiators. These experiments will allow us to further understand the mechanism of action of MI-4 and how the modifications to the molecule may affect inhibition activity.