MXE / O-PCE / ketamine metabolism

[palmanita]

I have entered their structures in SmartCyp and noticed something interesting: With both ketamine and the O-PCE (which becomes O-PCM first), the cyclohexane ring is attacked, while with MXE it is primarily the MeO.

Will the cyclohexane get opened and what might the resulting metabolites do? Thought norketamine would be the primary metabolite of ketamine, is smartcyp wrong here?

 

[aced126]

O-PCE isn't metabolised to O-PCM. I think what SmartCyp is trying to say is that the carbon you are referring to gets hydroxylated. I have never seen an instance where an ethyl is metabolised to a methyl. The whole alkyl chain tends to be cleaved off.

At the cyclohexane ring, the molecule is oxidised/dehydrogenated to a conjugated unsaturated ketone. https://en.wikipedia.org/wiki/Dehydronorketamine

Alternatively, the ring can be attacked by an electrophilic oxygen species (the carbon 1 away from the carbonyl is nucleophilic, the alpha carbon) and form an alpha hydroxylated metabolite. https://en.wikipedia.org/wiki/Hydroxynorketamine

 

[Solipsis]

Norketamine is the major metabolite of K, CYP 3A4 mostly demethylates K but I think it is also done by 2B6 for which it competes since 2B6 is also involved in the hydroxylation of the cyclohexanone ring.

Norketamine has ~33% activity but appears to be less 'psychedelic', it doesn't seem to be known what the further metabolites do on their own.

In SmartCyp the highest score should get the highest rank
http://www.farma.ku.dk/smartcyp/interpret.php

But they don't here... in any case for MeO's there is certainly an added site of metabolism that is apparently at least as much involved as cyclohexanone ring hydroxylation (and further ring oxy / dehydrogenation) but the N-alkyl remains a primary metabolism target.
In MXE its not primarily the MeO ; The N-ethyl of O-PCE and MXE is harder to metabolize for cyp, accounting for the longer duration / higher potency of the compounds compared to N-methyl counterparts.