Hydroxynorketamine (HNK), or 6-hydroxynorketamine, is a metabolite of ketamine which is formed by hydroxylation of its metabolite norketamine.[1] In
contrast to ketamine and norketamine, hydroxynorketamine is inactive as an anesthetic and psychostimulant.[2][3] In accordance, it has only very weak
affinity for the NMDA receptor (Ki = 21.19 µM and > 100 μM for (2S,6S)-hydroxynorketamine and (2R,6R)-hydroxynorketamine, respectively).[4]
However, hydroxynorketamine does still show biological activity, having been found to act as a potent and selective negative allosteric modulator of
the α7-nicotinic acetylcholine receptor (IC50 < 1 µM).[4] Moreover, (2S,6S)-hydroxynorketamine was tested and was found to increase the function
of the mammalian target of rapamycin (mTOR), a marker of the antidepressant activity of ketamine, far more potently than ketamine itself (0.05 nM for
(2S,6S)-hydroxynorketamine, 10 nM for (S)-norketamine, and 1,000 nM for (S)-ketamine (esketamine), respectively), an action that was observed to
correlate closely with their ability to inhibit the α7-nicotinic acetylcholine receptor.[5][6][7] This finding has led to a call of reassessment of
the understanding of the rapid antidepressant effects of ketamine and their mechanisms.[8] However, subsequent research has found that
dehydronorketamine, which is a potent and select antagonist of the α7-nicotinic acetylcholine receptor similarly to hydroxynorketamine, is inactive
in the forced swim test at doses up to 50 mg/kg in mice, and this is in contrast to ketamine and norketamine, which are effective at doses of 10 mg/kg
and 50 mg/kg, respectively.[9] This is likely due to the far lower potency of dehydronorketamine as an NMDA receptor antagonist in comparison.
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.The other way would be to think how acidic the alpha
H between these two EWG's would become and how easily a H-abstraction would be possible.(I am sure the nitro group would be enough on its own,the
ketone is there just for decoration 