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Ketamine Metabolites Enantioselectively Decrease Intracellular D-Serine Concentrations in PC-12 Cells.

Nagendra S Singh¹, Ewelina Rutkowska², Anita Plazinska²

¹Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, United States of America.

|April 21, 2016

Summary

This summary is machine-generated.

Ketamine metabolites reduce intracellular D-serine concentrations, crucial for NMDA receptor function. Specific metabolites, (2S,6S)- and (2R,6R)-hydroxynorketamine, show potent inhibition, aiding the design of novel neuroprotective agents.

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Study of the Functions and Activities of Neuronal K-Cl Co-Transporter KCC2 Using Western Blotting

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Published on: December 9, 2022

Area of Science:

Neuroscience
Pharmacology
Biochemistry

Background:

D-serine acts as an NMDA receptor co-agonist, vital for synaptic plasticity and neuronal function.
Elevated D-serine levels are implicated in neurodegenerative diseases like Alzheimer's and Parkinson's.
Ketamine metabolites have previously shown potential in modulating D-serine concentrations.

Purpose of the Study:

To investigate the inhibitory effects of various ketamine metabolites on intracellular D-serine concentrations.
To determine the IC50 values for ketamine metabolites affecting D-serine levels.
To establish structure-activity relationships and develop a pharmacophore model for D-serine modulators.

Main Methods:

PC-12 cells were incubated with a series of ketamine metabolites.
Concentration-dependent inhibition of intracellular D-serine was measured.
IC50 values were determined for each metabolite.

Main Results:

Ketamine metabolites significantly attenuated intracellular D-serine concentrations.
(2S,6S)-hydroxynorketamine and (2R,6R)-hydroxynorketamine exhibited the most potent inhibition (IC50 values of 0.18 ± 0.04 nM and 0.68 ± 0.09 nM, respectively).
Structural and stereochemical features influenced the inhibitory potency.

Conclusions:

Ketamine metabolites, particularly specific hydroxynorketamine enantiomers, effectively reduce intracellular D-serine.
These findings provide a basis for designing novel therapeutic agents targeting D-serine pathways for neurodegenerative diseases.
A preliminary 3D-QSAR/pharmacophore model was developed for future drug design efforts.