Hydroxynorketamine Blocks N-Methyl-d-Aspartate Receptor Currents by Binding to Closed Receptors

Jamie A. Abbott; Gabriela K Popescu

doi:10.1124/mol.120.119784

Hydroxynorketamine Blocks N-Methyl-d-Aspartate Receptor Currents by Binding to Closed Receptors

Jamie A. Abbott, Gabriela K Popescu

Molecular Pharmacology June 29, 2020 DOI: 10.1124/mol.120.119784 (opens in new tab)

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Characteristics	In vitro experimental study Peer reviewed
Population	Recombinant NMDA receptors expressed in human embryonic kidney 293 cells
Interventions	2R 6R-Hydroxynorketamine (HNK) Ketamine
Topics	Ketamine
Key findings	HNK blocked NMDA receptor currents with 100-fold-lower potency than ketamine (46 µM at pH 7.2), 10-fold-slower inhibition onset, slower apparent dissociation, weaker voltage dependence, and complete competition by magnesium, and was fully effective when applied to resting receptors. The authors propose these properties warrant further investigation of HNK as a possible therapeutic for NMDA receptor dysfunction.

Abstract

Ketamine, a dissociative anesthetic, is experiencing a clinical resurgence as a fast-acting antidepressant. In the central nervous system, ketamine acts primarily by blocking NMDA receptor currents. Although it is generally safe in a clinical setting, it can be addictive, and several of its derivatives are being investigated as preferable alternatives. 2R,6R-Hydroxynorketamine (HNK), a ketamine metabolite, reproduces some of the therapeutic effects of ketamine and appears to lack abuse liability. Here, we report a systematic investigation of the effects of HNK on macroscopic responses elicited from recombinant NMDA receptors expressed in human embryonic kidney 293 cells. We found that, like ketamine, HNK reduced NMDA receptor currents in a dose-, pH-, and voltage-dependent manner. Relative to ketamine, it had 100-fold-lower potency (46 µM at pH 7.2), 10-fold-slower inhibition onset, slower apparent dissociation rate, weaker voltage dependence, and complete competition by magnesium. Notably, HNK inhibition 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 NMDA receptors are excitatory ion channels with fundamental roles in synaptic transmission and plasticity, and their dysfunction associates with severe neuropsychiatric disorders. 2R,6R-Hydroxynorketamine, a metabolite of ketamine, mimics some of the neuroactive properties of ketamine and may lack its abuse liability. Results show that 2R,6R-hydroxynorketamine blocks NMDA receptor currents with low affinity and weak voltage dependence and is effective when applied to resting receptors. These properties highlight its effectiveness to a subset of NMDA receptor responses and recommend it for further investigation.

Comparable studies

Other preclinical and animal studies on ketamine, most cited first.

Study	Year	Design
mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats	2010	Observational study
Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats	1997	Dose-response study with microdialysis and behavioral testing
NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice	2016	Preclinical study
The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats	1983	Experimental study
R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice	2015	Experimental study

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