Hydroxynorketamine Pharmacokinetics and Antidepressant Behavioral Effects of (2,6)- and (5R)-Methyl-(2R,6R)-hydroxynorketamines

Abstract

(R,S)-Ketamine is rapidly metabolized to form a range of metabolites in vivo, including 12 unique hydroxynorketamines (HNKs) that are distinguished by a cyclohexyl ring hydroxylation at the 4, 5, or 6 position. While both (2R,6R)- and (2S,6S)-HNK readily penetrate the brain and exert rapid antidepressant-like actions in preclinical tests following peripheral administration, the pharmacokinetic profiles and pharmacodynamic actions of 10 other HNKs have not been examined. We assessed the pharmacokinetic profiles of all 12 HNKs in the plasma and brains of male and female mice and compared the relative potencies of four (2,6)-HNKs to induce antidepressant-relevant behavioral effects in the forced swim test in male mice. While all HNKs were readily brain-penetrable following intraperitoneal injection, there were robust differences in peak plasma and brain concentrations and exposures. Forced swim test immobility rank order of potency, from most to least potent, was (2R,6S)-, (2S,6R)-, (2R,6R)-, and (2S,6S)-HNK. We hypothesized that distinct structure–activity relationships and the resulting potency of each metabolite are linked to unique substitution patterns and resultant conformation of the six-membered cyclohexanone ring system. To explore this, we synthesized (5R)-methyl-(2R,6R)-HNK, which incorporates a methyl substitution on the cyclohexanone ring. (5R)-Methyl-(2R,6R)-HNK exhibited similar antidepressant-like potency to (2R,6S)-HNK. These results suggest that conformation of the cyclohexanone ring system in the (2,6)-HNKs is an important factor underlying potency and that additional engineering of this structural feature may improve the development of a new generation of HNKs. Such HNKs may represent novel drug candidates for the treatment of depression.

Enantioselective CE–MS analysis of ketamine metabolites in urine

“…More (2S,6S)-6HNK than (2R,6R)-6HNK was formed. The same was found previously in mice [8]. In human plasma collected after treatment with KET and then analyzed with an achiral LC-MS method, 6HNK was described in the literature as the major circulating metabolite ((2S,6R); (2R,6S)-6HNK > (2S,6S); (2R,6R)-6HNK) followed by (2S,5S); (2R,5R)-5HNK, (2S,4R); (2R,4S)-4HNK, (2S,4S); (2R,4R)-4HNK, and (2S,5R); (2R,5S)-5HNK.…”

“…Hydroxynorketamine (HNK) stereoisomers are metabolites of KET and have become a focus of interest for drug repurposing, as they have shown strong antidepressant effects, whereas typical side effects known from the treatment with KET, such as dissociation and substance abuse, were absent [4,8,9]. Preclinical studies have revealed the (2R,6R)-6HNK enantiomer as having the strongest antidepressant effect followed by (2S,6R)-6HNK, (2R,6S)-6HNK, and (2S,6S)-6HNK [8]. These enantiomers arise when KET is stereoselectively metabolized by cytochrome P450 enzymes.…”

Pharmacogenetic and drug interaction aspects on ketamine safety in its use as antidepressant ‐ implications for precision dosing in a global perspective

“…However, Zanos’ hypothesis has been questioned as many researchers believe that the NMDA receptor blockage is involved in the antidepressant effects of ketamine and its metabolites 31 . Interestingly, a recent preclinical study in mice suggested that the potency of the HNKs is associated with the conformation of the cyclohexanone ring system in the (2, 6)‐HNKs 82 . However, the therapeutic antidepressant potential of (2, 6)‐HNK observed in preclinical studies has not been evaluated in a prospective clinical study.…”

“…31 Interestingly, a recent preclinical study in mice suggested that the potency of the HNKs is associated with the conformation of the cyclohexanone ring system in the (2, 6)-HNKs. 82 However, the therapeutic antidepressant potential of (2, 6)-HNK observed in preclinical studies has not been evaluated in a prospective clinical study.…”

Psychedelic drugs take on depression

“…Gould's team has identified one such molecule, called (2R,6R)-hydroxynorketamine. In animal studies 5 , the metabolite can produce ketamine-like antidepressant effects all on its own, but without inducing the dizzying high that causes some people to misuse ketamine. Gould and his colleagues have launched a phase I trial of the metabolite in healthy volunteers, and hope to begin phase II studies in treatment-resistant depression in the coming year.…”