Pharmacological evaluation of clinically relevant concentrations of (2R,6R)-hydroxynorketamine

• Published in: Neuropharmacology 2019-07, Vol.153, p.73-81
• Main Authors: Shaffer, Christopher L., Dutra, Jason K., Tseng, Wei Chou, Weber, Mark L., Bogart, Luke J., Hales, Katherine, Pang, Jincheng, Volfson, Dmitri, am Ende, Christopher W., Green, Michael E., Buhl, Derek L.
• Format: Article
• Language: English
• Subjects: (2R,6R)-hydroxynorketamine; Animals; Antidepressive Agents - metabolism; Antidepressive Agents - pharmacology; Cells, Cultured; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Depression; Dogs; Drug Evaluation, Preclinical - methods; Humans; Ketamine; Ketamine - analogs & derivatives; Ketamine - metabolism; Ketamine - pharmacology; Madin Darby Canine Kidney Cells; Male; Mice; Mice, Transgenic; N-methyl-d-aspartate receptor; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - metabolism; α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2019.04.019

Ketamine is a rapid-onset antidepressant whose efficacy long outlasts its pharmacokinetics. Multiple studies suggest ketamine's antidepressant effects require increased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-dependent currents, which have recently been exclusively attributed to its N-methyl-d-aspartate receptor-inactive metabolite (2R,6R)-hydroxynorketamine ((2R,6R)-HNK). To investigate this AMPAR-activation claim further, we estimated and evaluated preclinically and clinically relevant unbound brain HNK concentrations (Cb,u). (2S,6S)-HNK and (2R,6R)-HNK were novelly synthesized, and their neuropharmacokinetic profiles were determined to project relevant Cb,u. Using concentrations (0.01–10 μM) bracketing the pertinent cross-species Cb,u, both compounds' AMPAR modulation was assessed in vitro by electrophysiological recordings and GluA1 surface expression. Neither (2S,6S)-HNK nor (2R,6R)-HNK bound orthosterically to or directly functionally activated AMPARs. (2R,6R)-HNK failed to evoke AMPAR-centric changes in any electrophysiological endpoint from adult rodent hippocampal slices. Conversely, time- and concentration-dependent increases in GluA1 expression occurred only with (2R,6R)-HNK (≥0.1 μM at ≥90 min). The (2R,6R)-HNK concentrations that increased GluA1 expression are consistent with its maximal Cb,u (0.92–4.84 μM) at reportedly efficacious doses of ketamine or (2R,6R)-HNK in mouse depression models, but ≥3-fold above its projected maximal human Cb,u (≤37.8 ± 14.3 nM) following ketamine's clinically antidepressant infusion. These findings provide insight into the observed AMPAR-affecting (2R,6R)-HNK concentrations versus its exposures attained clinically at an antidepressant ketamine dose. To optimize any clinical study with (2R,6R)-HNK to fully assess its translational pharmacology, future preclinical work should test (2R,6R)-HNK concentrations and/or Cb,u of 0.01–0.1 μM to parallel its projected human Cb,u at a clinically antidepressant ketamine dose.