A slippery question. As people have noted, ketamine is chiral and the two isomers have totally different effects. Some people seem to prefer esketamine while other feel that the raecemate being 50% (R) ketamine is important since the latter acts on both the VMAT2 and PMAT transports i.e. increases levels of extracellular dopamine.
Long, long ago when MXE was just an idea, the very first step was to resolve ketamine to test the subjective effects of each isomer. Now others imbibed but most described (R) ketamine as being similar to cocaine and since I loathe cocaine, I abstained.
The IMPORTANT thing about MXE was to find a compound that was more potent but had a similar ratio of activities between the two isomers. Lest we forget, it took quite a few attempts with lots of slightly worrying first-into-man studies to find the right one. I think people forget that - it wasn't simply a case of 'well, this will do' but 'what is the very best possible'? Also MXE was a novel compound and I believe the inventor is named in the patent.
Since then I have shared the obscure GB patent (GB-1202834-A) covering what has been described as CXME (2-chloro-5-methoxy) i.e. it overlays both ketamine AND MXE. Why a US company would choose to go with a GB patent isn't clear. Possibly many things influenced the decision, none of them too ethical.
But don't forget that it's entirely possible to produce related compounds that are at one end of the spectrum ot the other, the 'magic' is in that ratio (unless you prefer the pure NMDA activity). If so, it's worth remembering that dizocipline was offered as an RC for a while but the reports are frankly quite scary. Now it even gets a bit more complex because a French team synthesized and tested TCP (tenocyclidine) homologues (FR-2858934-A1) and it was interesting to note that the ketone moiety seen in both K and MXE could be replace with a (chiral) methyl side-chain. They located two sites on the NMDA receptor and carefully tested to see the ratios between those two subtypes in each case.
One assumes that the aromatic could equally have been a (ring-substituted) benzene BUT nobody knows for sure. For example, I don't think the French researchers went back to test the ratio of dizocipline which is a shame because maybe it would hint at what makes that stuff almost universally disliked.
It seems the more we look at the arylcyclohexylamines, the more complex their activity is revealed to be and the more complex deriving a QSAR has become.
I think the one thing we have learnt is that the ketone is important not only because it affects the affinity but also because it alters the pharmokinetics. Without it, some of those compounds seem to act for far longer than most people are willing to endure.
