Why 2-methoxydeschloroketamine & ethylnorketamine were disappointing

[adder]

I've been recently looking into arylcyclohexanamine derivatives that are potent mu opioid agonists. I thought that I'd possibly figured out why 2-methoxydeschloroketamine and ethylnorketamine (2-MK and ENK) were disappointing for some people, so I decided to share my thoughts.

Although there is no evidence that ketamine acts as a mu opioid receptor agonist, I think the possibility that it is a weak mu opioid agonist (a very weak one) is very real. I derive the hypothesis based on the SAR of opioid 4-oxo-arylcyclohexanamines. The most potent compounds in the series as opioids seem to be those with p-chloro or p-bromo substitution, ortho-substituted analogues are much weaker, but still some of them are around the potency of pethidine. However, it's a bit difficult to draw a perfect relationship from the numbers in the paper which I'm basing this on. The fact is that these compounds are active as analgesics, this is still unknown terrain though.

For best opioid activity the amine should be tertiary with two methyl groups (as in bromadol for instance). Ketamine and 2-MK have secondary amines with one methyl group, ENK has one ethyl group, so out of these three ENK would be least likely to be active as an opioid agonist; compounds with the piperidine ring retained are definitely passable as opioids in my opinion, the simplest one 4-oxo-PCP is an active opioid. But the problem with 2-MK is the o-methoxy group that seems to serve to decrease the activity vs. o-chloro (p-chloro is ~6x o-chloro, p-methoxy is around the potency of o-chloro, so o-methoxy may be too weak to be any good at all), perhaps even more if we're dealing with compounds lacking the 4-oxo (or it doesn't matter at all if ketamine isn't an opioid agonist).

Aside from the fact that products sold as 2-MK and ENK in many cases didn't really contain those compounds, it's possible that 2-MK and ENK are simply both inferior to ketamine as opioid agonists. For me the magic of dissociatives mostly lies in their ability to cause dissociation. For the most of my teenage life I was sadly on opioids all the time, so even if ketamine has some opioid effects, it's impossible for me to have felt them. Compounds with carbonyl group at C4 have reduced NMDAR antagonist properties, but those with carbonyl group at C2 are still active as dissociatives and they're possibly also opioids (I had a report about 2-oxo-PCP feeling "analgesic", but it's the same as some people here on Bluelight mentioning that methoxetamine felt to them as if it was an opioid agonist, and meta substitution gives results inferior to both para and ortho, that's no proof).

All numbers and assumptions are based on J. Med. Chem 1980, 23, 424-430.

 

[amanitadine]

I've been recently looking into arylcyclohexanamine derivatives that are potent mu opioid agonists. I thought that I'd possibly figured out why 2-methoxydeschloroketamine and ethylnorketamine (2-MK and ENK) were disappointing for some people, so I decided to share my thoughts.
-----------------------------------

Aside from the fact that products sold as 2-MK and ENK in many cases didn't really contain those compounds, it's possible that 2-MK and ENK are simply both inferior to ketamine as opioid agonists. For me the magic of dissociatives mostly lies in their ability to cause dissociation.

Bonafide (tested, and synthesized) 2-MK and ENK were disappointing to basically everyone....and not because they lacked opioid effects, but because they lacked virtually any effect, unless ridiculous doses were taken, and even then the effects were very, very mild..

The only positive reports were in your "PCP analogs" post....and unsurprisingly many of your other reports didn't match up to actual trials...

I am interested in your conjecture on the potential for opiodergic effects from arylcyclohexylamines, but when it is conjecture let's paint is as that, yeah?

 

[blueberries]

Perhaps 2-meth-fluoro and 2-meth-chloro could be candidates for a better ketamine? The trick would be to get it as heavy as Chloro on it's own but not too spacious, maybe -di or -tri fluoromethyl?

Also, the first time I tried Ethketamine it was similar to S-Ketamine in potency but no hole was to be found so perhaps the balance between the amine and the 2-sub is the key. Meaning 16 on the amine and 17 on the 2 position is key. So if one was to inflate either side it would have to be balanced as such. Ethyl may be more potent but you would need an extra methyl on the chloro to counter balance it.

Maybe even adding a deuterium to the methyl on the amine of ketamine would produce better results so 17 : 17.

 

[adder]

Bonafide (tested, and synthesized) 2-MK and ENK were disappointing to basically everyone....and not because they lacked opioid effects, but because they lacked virtually any effect, unless ridiculous doses were taken, and even then the effects were very, very mild..

The only positive reports were in your "PCP analogs" post....and unsurprisingly many of your other reports didn't match up to actual trials...

I am interested in your conjecture on the potential for opiodergic effects from arylcyclohexylamines, but when it is conjecture let's paint is as that, yeah?

It seems that your 2-MK and ENK weren't real if they lacked virtually any effect. These are not inactive compounds. Anyway, I'm not saying that ketamine is an opioid, I'm saying it might be. Well, there's an evidence it isn't at all, then we can move to the interactions between the opioid system and NMDA receptors.

Also, the first time I tried Ethketamine it was similar to S-Ketamine in potency but no hole was to be found so perhaps the balance between the amine and the 2-sub is the key. Meaning 16 on the amine and 17 on the 2 position is key. So if one was to inflate either side it would have to be balanced as such. Ethyl may be more potent but you would need an extra methyl on the chloro to counter balance it.

It doesn't really work that way. While sometimes you can really hit the spot where adding a larger substituent makes a compound inactive or barely active compared to its parent compound due to steric hindrance, it's not a case here. Although arylcyclohexanamines don't take many substitutions well (e.g. vs. stimulant amphetamines), various changes are well tolerated on the amine. I'm implying that a methyl group on nitrogen at least better potentiates opioids than an ethyl group, but that is related to the SAR of various opioids and not really to the size of a molecule, but I get your point. I've heard a lot of vendors sold false 2-MK and ENK, I don't know why, because they're not harder to synthesize than plain ketamine. PCP isn't really sought after either, but it looks like the RC market will take up anything with a fancy name.

Trifluoromethyl on the ortho position would likely be active and if not comparable to ketamine, then stronger, but you don't really see much compounds with such functional groups released on a large scale, because the synthesis is cost-ineffective when you can get compounds of similar potency with fewer costs. So even if someone eventually synthesizes 2-trifluoromethyldeschloroketamine or a similar compound, I don't think that too many will have an opportunity to try it, similarly to 2C-TFM or DOTFM.

 

[kingbuyer]

I found n-ethylnorketamine to be enjoyable.

 

[mad_scientist]

Trifluoromethyl on the ortho position would likely be active and if not comparable to ketamine, then stronger...

I've been told the 2-fluoro analogue of ketamine is pleasant and with a similarly fun and sociable kind of high to ketamine itself, though with lower potency and generally less intense overall. The bromo compound is also known, though I have not heard any bioassay reports. Trifluoromethyl would be interesting as there are several examples where replacing Cl with CF3 results in similar but generally "improved" activity to the parent compound (see e.g. mCPP --> TFMPP, 2C-C --> 2C-TFM) however I've never heard of this substitution being tried on ketamine, likely due to the much less available precursors that would be required for synthesis.

 

[Incunabula]

It seems that your 2-MK and ENK weren't real if they lacked virtually any effect. These are not inactive compounds.

2-MK is actually VERY close to being completely inactive. And no, it's not because some one sold fake stuff. Plenty of top notch vendors sold the real deal, and it is agreed by EVERY ONE who tried it, that it's probably the most shitty lacking RC to ever have been made and put for sale.

You have to face consensus reality, Adder. 2-MK is worthless shit.

 

[amanitadine]

^ ditto. The two products I tried were verified real, and virtually inactive, until very high doses were consumed, and even then it was still shite.

The SAR makes sense. The reality did not. I distinguish between the two. Seems important, no?

 

[adder]

Well then, I thought that I had only seen the spectra for ethylnorketamine. I won't insist as I've been on a hefty dose of clonazepam then, so it's very possible that the effects were much less pronounced and it was harder to tell them apart. Diphenidine did next to nothing to me at the doses that gave good effects for most people reporting here.

The SAR makes sense. The reality did not. I distinguish between the two. Seems important, no?

Embarrassed, I must now say that the SAR actually says that 2-MeO is worthless compared to 2-halo. I'm basing this off the results for 4-oxoarylcyclohexanamines as analgesics, but it's possible to draw some analogy anyway. In methoxetamine, N-ethyl is deciding on potency and 3-methoxy is rather deciding on the pharmacodynamic profile, I guess. The reason why I opted for 2-methoxydeschloroketamine in the first place was because of the calculated methoxy group electronegativity, but I was a rookie back then (well, technically I still am), I didn't count in hydrophobicity among other things, which seems absolutely crucial here if methoxy doesn't substitute at all for chloro, and my mate that did the chemistry part wasn't much into pharmacology.

It's weird to me though that the vendors who released this stuff in the past didn't run some tests to see whether the stuff is worth the price. Like I previously wrote, I know that vendors will take up anything with a fancy name especially if it's related to highly praised drugs, but it's beyond my comprehension that people can sell nothing for any price. Ethylnorketamine can still be bought from some sites last time I checked, but there really is no 2-MK, so that makes a lot of sense. Although I honestly didn't earn a single cent off these and it wasn't my intention to bring any drugs into the RC market or any market for that matter, I feel really stupid for letting vendors rip off people, and I'm really sorry for that.

 

[blueberries]

What I noticed was that 2-MK from the usual vendors was very similar to the NEK. I had some part in how the NEK was distributed, which I am kind of sorry for.

Just before the release of 2-MK, I posted on the 2-MK thread that NEK was already on the market from an asian vendor (which I had already tried) then suddenly all the usual UK vendors stared offering NEK instead of 2-MK (if you look back at the original thread you can see that there was a deleted post but still I was quoted by someone else which remains there). It was just a theory but I think the UK vendors were offering 2-MK as NEK instead as it had a much more exciting look to it. The NEK I had before from the asian vendor was markedly different to both the 2-MK and the NEK offered by UK vendors.

Still though this doesn't change the fact that the original NEK was fairly poor and I couldn't reach a hole but it's potency was a lot higher than the 2-MK and NEK offered by UK vendors.