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

Pharmacological evaluation of clinically relevant concentrations of (2R,6R)-hydroxynorketamine. Neuropharmacology. 2019 Apr 20;: Authors: Shaffer CL, Dutra JK, Tseng WC, Weber ML, Bogart LJ, Hales K, Pang J, Volfson D, Am Ende CW, Green ME, Buhl DL Abstract 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 ex...
Source: Neuropharmacology - Category: Drugs & Pharmacology Authors: Tags: Neuropharmacology Source Type: research