PT  - JOURNAL ARTICLE
AU  - Jamie A Abbott
AU  - Gabriela K. Popescu
TI  - Hydroxynorketamine Blocks NMDA Receptor Currents by Binding to Closed Receptors
AID  - 10.1124/mol.120.119784
DP  - 2020 Jan 01
TA  - Molecular Pharmacology
PG  - mol.120.119784
4099  - http://molpharm.aspetjournals.org/content/early/2020/06/29/mol.120.119784.short
4100  - http://molpharm.aspetjournals.org/content/early/2020/06/29/mol.120.119784.full
AB  - Ketamine, a dissociative anesthetic, is experiencing a clinical resurgence as fast-acting antidepressant. In the central nervous system, ketamine acts primarily by blocking NMDA receptor currents. Although it is generally safe in clinical setting, it can be addictive and several of its derivatives are investigated as preferable alternatives. Hydroxynorketamine, a ketamine metabolite, reproduces some of the therapeutic effects of ketamine and may lack abuse liability. The molecular mechanisms by which ketamine and its metabolites exert their neuroactive properties are complex and incompletely understood. Here we report a systematic investigation of the effects of hydroxynorketamine on recombinant NMDA receptor currents. We found that like ketamine, hydroxynorketamine reduced NMDA receptors in a dose-, pH-, and voltage-dependent manner. Although relative to ketamine, it had 100-fold lower potency (46 μM at pH 7.2) due to slower inhibition onset, hydroxynorketamine also had ~3-fold slower apparent dissociation rate, weaker voltage-dependence, and was less effectively outcompeted by magnesium. Notably, it was fully effective when applied to resting receptors. These results revealed unexpected properties of hydroxynorketamine that warrant its further investigation as a possible therapeutic in pathologies associated with NMDA receptor dysfunction.SIGNIFICANCE STATEMENT Ketamine, a dissociative anesthetic, is experiencing a clinical resurgence as fast-acting antidepressant. In the central nervous system, ketamine acts primarily by blocking NMDA receptor currents. Although it is generally safe in clinical setting, it can be addictive and several of its derivatives are investigated as preferable alternatives. Hydroxynorketamine, a ketamine metabolite, reproduces some of the therapeutic effects of ketamine and may lack abuse liability. The molecular mechanisms by which ketamine and its metabolites exert their neuroactive properties are complex and incompletely understood. Here we report a systematic investigation of the effects of hydroxynorketamine on recombinant NMDA receptor currents. We found that like ketamine, hydroxynorketamine reduced NMDA receptors in a dose-, pH-, and voltage-dependent manner. Although relative to ketamine, it had 100-fold lower potency (46 µM at pH 7.2) due to slower inhibition onset, hydroxynorketamine also had ~3-fold slower apparent dissociation rate, weaker voltage-dependence, and was less effectively outcompeted by magnesium. Notably, it was fully effective when applied to resting receptors. These results revealed unexpected properties of hydroxynorketamine that warrant its further investigation as a possible therapeutic in pathologies associated with NMDA receptor dysfunction.