Abstract: Ketamine has risen to prominence in the last 15 years as a fast-acting therapeutic for treatment-resistant depression. However, concerns over the side effects associated with ketamine treatment limit its clinical use. A metabolite of ketamine, (2R,6R)-hydroxynorketamine (HNK)), has been found to possess rapid antidepressant-like activity in multiple murine models of depression. Moreover, (2R,6R)-HNK has not been found to possess sensory dissociation or drug abuse properties in animal models predictive of psychotomimetic and abuse potential side effects, respectively. Unlike ketamine, which potently blocks the NMDA receptor, (2R,6R)-HNK has been shown to have low affinity to the NMDA receptor. Instead, it may act acutely by increasing excitatory (glutamate) neurotransmission activating neuronal AMPA receptors. Preclinical range-finding and GLP toxicological studies have identified a high therapeutic index. Minor effects on the respiratory, cardiovascular, and central nervous systems were observed only at the highest doses (&gt;90 mg/kg iv), which rapidly resolved. An updated synthesis for (2R,6R)-HNK allows for cGMP-compliant manufacture on kilogram scale, with significant improvements in yield and cost savings.

Synthesis, preclinical efficacy, and toxicology of (2R,6R)-hydroxynorketamine, a therapeutic candidate for treatment-resistant depression

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.