Ketamine Metabolites Enantioselectively Decrease Intracellular D-Serine Concentrations in PC-12 Cells.
D-Serine is an endogenous NMDA receptor co-agonist that activates synaptic NMDA receptors modulating neuronal networks in the cerebral cortex and plays a key role in long-term potentiation of synaptic transmission. D-serine is associated with NMDA receptor neurotoxicity and neurodegeneration and elevated D-serine concentrations have been associated with Alzheimer's and Parkinsons' diseases and amyotrophic lateral sclerosis. Previous studies have demonstrated that the ketamine metabolites (rac)-dehydronorketamine and (2S,6S)-hydroxynorketamine decrease intracellular D-serine concentrations in a concentration dependent manner in PC-12 cells. In the current study, PC-12 cells were incubated with a series of ketamine metabolites and the IC50 values associated with attenuated intracellular D-serine concentrations were determined. The results demonstrate that structural and stereochemical features of the studied compounds contribute to the magnitude of the inhibitory effect with (2S,6S)-hydroxynorketamine and (2R,6R)-hydroxynorketamine displaying the most potent inhibition with IC50 values of 0.18 ± 0.04 nM and 0.68 ± 0.09 nM. The data was utilized to construct a preliminary 3D-QSAR/pharmacophore model for use in the design of new and more efficient modulators of D-serine.
Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, United States of America.
Nagendra S
NS
Singh
Department of Biopharmacy, Medical University of Lublin, Lublin, Poland.
Ewelina
E
Rutkowska
Department of Biopharmacy, Medical University of Lublin, Lublin, Poland.
Anita
A
Plazinska
Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, United States of America.
Mohammed
M
Khadeer
Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, United States of America.
Ruin
R
Moaddel
Department of Biopharmacy, Medical University of Lublin, Lublin, Poland.
Krzysztof
K
Jozwiak
Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, United States of America.
Michel
M
Bernier
Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, United States of America.
Irving W
IW
Wainer
D026962:Amino Acid Transport System ASC / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D007649:Ketamine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015778:Minor Histocompatibility Antigens; D008958:Models, Molecular; D016716:PC12 Cells; D021381:Protein Transport; D051381:Rats; D012694:Serine / Q000378:metabolism*; D013237:Stereoisomerism
D026962:Amino Acid Transport System ASC; D015778:Minor Histocompatibility Antigens; C498849:Slc1a5 protein, rat; D012694:Serine; D007649:Ketamine