Featured Paper of the Month – September 2022
Published in Molecular Psychiatry by Jordi Bonaventura and Michael Michaelides, et al. of the NIDA IRP Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit.
The use of racemic ketamine and the FDA approval of (S)-ketamine are promising developments for the treatment of depression. Nevertheless, racemic ketamine and (S)-ketamine are controlled substances with known abuse potential and their use is associated with undesirable side effects. For these reasons, research efforts have focused on identifying alternatives. One candidate is (2R,6R)-hydroxynorketamine ((2R,6R)-HNK), a ketamine metabolite that in animal studies lacks the dissociative and abuse properties of ketamine while retaining its antidepressant-like behavioral efficacy. (2R,6R)-HNK’s mechanism of action however is unclear. We tested (2R,6R)-HNK against >30,000 human proteins and did not find any (2R,6R)-HNK-protein interaction indicating it has a highly inert pharmacological profile. (2R,6R)-HNK also did not share any pharmacological or behavioral profile similarities with ketamine or its enantiomers. Given its pharmacological profile, we predict that (2R,6R)-HNK will exhibit a favorable safety profile in clinical trials, and we must wait for clinical studies to determine its antidepressant efficacy.