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Structure-Activity Relationships (SAR) of NMDA open-channel blockers

cosmotroniks

cosmotroniks

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I'm interested in studying the possibilities about detailed relationships between overall shape/structure of these compounds and how they relate to binding affinities, bioavailability, pharmacokinetics/pharmacodynamics, and psychologically/physically manifested effects (not to mention the potential spiritual implications)...

The first area that comes to mind is that of the arylcyclohexylamine derivatives,
the most famous of course being phencyclidine.

I've dug up quite a bit of research/journal articles over the years, and from what I can tell, it seems that maintaining a six-member ring structure all 'round seems to be the only way that works well in most cases.

According to some of what I've found/read, the replacement of the phenyl moiety with another functional group can have interesting implications - for example, replacing the phenyl group with thienyl (yielding tenocyclidine [1-(1-(2-Thienyl)cyclohexyl)piperidine], results in a considerable increase in potency with more preference for NMDA, and more stimulant/dopaminergic effects, with less sigma activity.

replacement with n-ethyl (yielding PCE/CI-400, developed by Parke-Davis in Detroit during their research into these compounds) results in more potency as well.

Then there's the whole issue of substitutions at various odd positions on the aromatic ring or the cyclohexyl ring... all interesting stuff to me..

If anybody has anything to add to this/comments/constructive criticisms about it, please feel free to join in.

I have access to various advanced chemistry/bioinformatics software, including ChemOffice Ultra and AutoDock, so I might make 2D and/or 3D models and do docking/binding analysis against target protein residues on a series of them.

On a side note: I don't condone the illicit synthesis of these drugs, because they can be very dangerous when either misused or poorly manufactured... not to mention that the dissociatives are a class of drugs most people would do best to avoid altogether. They are IMHO the most powerful psychoactive compounds in existence. (don't get me wrong, phenethylamines and tryptamine psychedelics can be very powerful as well, but I don't think they're quite so dark and 'heavy' the way dissociatives can be...) They can take you to places of extreme cosmic-floaty euphoria, and they can also take you straight to hell; trust me, I've had both types of experience with these drugs. I would not recommend PCP or even DXM to anyone else. I try to stay away from the dust these days, it just got to be a nightmare after a while (never tried K, but I'm sure it's similar in many aspects).

Here's a couple of interesting resources:

http://www.erowid.org/archive/rhodium/chemistry/pcp/sar.html

http://www.erowid.org/archive/rhodium/chemistry/pcp/pcp_index.html

http://www.erowid.org/archive/rhodium/chemistry/pcp.shulgin.html

http://www.ncbi.nlm.nih.gov/pubmed/17968862

http://www.timothywyllie.com/PCP.htm [I found this to be a quite interesting read]

http://pubs.acs.org/doi/abs/10.1021/jm00087a020


check 'em out... and as I said, I do not personally condone the actual synthesis of these, much less the illicit sale and distribution because it's just too dangerous IMHO... most of the aforementioned resources contain detailed synth info, but I am not posting them with the motivation of encouraging use/manufacture; rather I'm just interested in the structure-activity relationships and such as an intellectual exercise, and to satisfy my own selfish curiosity.
 
The replacing the aromatic ring does have an impact on the quality of the experience- replacing with a 2-thienyl increases dopaminergic activity, but also removes any opiate affinity (tiletamine, the thienyl equivalent of ketamine is a cold, quite disturbing dissociative). Using a 3-methoxyphenyl increases opiate affinity and is considerably less confusing than the plain unsubstituted phenyl (personal exp comparing PcP/3-methoxyPCP; PCE/3-methoxyPCE and 2-phenyl-2-ethylaminocyclohexanone/ketamine/2-(3-methoxyphenyl)-2-(N-ethylamino)cyclohexanone). I know ket has an N-methyl as opposed to the other N-ethyls, but that just seems to alter potency and not the qualitative feel of the drug, although PCE is def different from PCP, but that's replacing a piperidyl amine function with an alkylamino
 
This is 100% my area of expertise but im not going to offer any insight because ive been treated really poorly by other users here. Its a shame because i want to help you as i enjoy these sorts of discussions. sorry.
 
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fireball said:
This is 100% my area of expertise but im not going to offer any insight because ive been treated really poorly by other users here. Its a shame because i want to help you as i enjoy these sorts of discussions. sorry.
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And worse yet a rival drug dealer;)
 
fireball said:
This is 100% my area of expertise but im not going to offer any insight because ive been treated really poorly by other users here. Its a shame because i want to help you as i enjoy these sorts of discussions. sorry.
Click to expand...

None of the users who posted in this thread were the ones who treated you "really poorly" if you are referring to the tox-thread. Why take it out on this thread if you, as you claim, can add to it? I'm not the only one who is interested in this topic. Hopefully you let your grudge go and contribute.

fryingsquirrel said:
And worse yet a rival drug dealer;)
Click to expand...

Comments like this degrade the quality of the ADD board, regardless if you're serious or not. Can we all grow up and stay on topic?
 
As for SARS, from my very, very limited knowledge, here is a process of elimination. Please feel free to add, subtract, multiply, divide, or uglify ;)

Ketamine's magic seems to be dependent on:
- A chiral centre, and a racemic mix
- A halogenated (or perhaps chlorine specific) aromatic ring
- A Ketone on the Cyclohexyl ring
- Ammonia on the other side of the cyclohexyl spiral

(apologies for my byzantine discriptions, I'm no chemist ;))

It seems that the removal of even one of these four things results in something that is far different (and, in my subjective opinion, inferior) than Ketamine.

Do we have any info on Ketamine analogues that differ only by choice of halogen?

Do we have any info on Ketamine analogues that differ only on the chain-substitution on the amine?
 
From what I recall, n-ethyl-norketamine should be more potent than ketamine. Not sure about the effects though. Potency does not always equal quality.

As for the ortho-chloro-substitution, I've been wondering... Something between a hydrogen and a chlorine would be a fluorine. So maybe a fluorine analogue could be worth a shot? Not sure if it would work though, fluorine seems to be different than other halogens in some respects. But perhaps some day someone will make it and then we'll know...
 
I've found some interesting results with analysis using ALOGPS (haven't done any dockings yet; I need to get off my lazy rear and do more work on this)
on a compound called 1-(1-(9H-fluoren-9-yl)cyclohexyl)piperidine...

or, more simply it could be known as FCP, I guess.

Molecular formula is C24H29N, mol. wt 331.49 g/mol.

I'd guess a potency somewhere between 6-20 mg for fairly profound effects.

Could be wrong, of course. I've never synthesized it or tasted it. It exists (to me) only on my computer in electronically modeled form.

I can't claim it as an original either; it was apparently synthesized in the late fifties or early sixties along with about 60 or so other compounds by Parke-Davis during their arylcyclohexylamine dissociative anesthetic research. I have the original journal article.
 
dread said:
From what I recall, n-ethyl-norketamine should be more potent than ketamine. Not sure about the effects though. Potency does not always equal quality.

As for the ortho-chloro-substitution, I've been wondering... Something between a hydrogen and a chlorine would be a fluorine. So maybe a fluorine analogue could be worth a shot? Not sure if it would work though, fluorine seems to be different than other halogens in some respects. But perhaps some day someone will make it and then we'll know...
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Correct me if I'm wrong, but isn't norketamine simply de-methylated K? So The compound you refer to would simply be ethylketamine.

What seems to be the pattern is that longer chains (at least as long as ethyl) on the amine mainly affect potency and not much else. That said, the consensus seems to be that the propyl analogue of PCP is a rather uninteresting compound (personally, I found it rather yucky). However, I maintain what I note above, that PCP (and its analogues) and Ketamine (and its analogues) seem to be two very different animals.

---

Thanks for the link, Hugo :) <3

However, that link raises one problem I'd like to adress here which I've seen raised in other threads on the same issue. There seems to be a confusion between anaesthesic action and analgesic action.

Anaesthesia - literally, "no sensing", is NOT a pain-reducing effect primarily, but rather the effect of simply shutting off sensory input, be it painful or otherwise. It feels as though one was swimming in xylocaine. I think its purest form is simply the main (and only?) action of N2O.

Analgesia is painkilling properties - basically an effect that one can compare to the effects of NSAIDs, however it does not necessarily entail euphoria.

I noticed that many (most?) PCP analogues ARE NOT anaesthetic. I cannot comment 100% on whether they (the few I've tried) are analgesic or not (but probably are due to opioid activity).

Ketamine (particularly the racemate) IS anaesthetic and, IMO, this property is important for its entheogenic side. Think sensory-isolation tanks. It is also mildly analgesic and slightly euphoric (but the latter is subjective for the most part).

Plain PCP IS anaesthetic AND analgesic AND euphoric.

From what I've read, Tiletamine IS Anaesthetic, AND analgesic, but NOT euphoric.

Morphine (to give another example) is definitely analgesic AND euphoric, but NOT anaesthetic.

Hope we can all agree on this, because I noticed a lot of people confuse the two and when talking about SARs it is rather miring.

EDIT: Judging by what FnB suggested in his new TR, it seems that phenyl substitution at the 3' position is primarily responsible for increasing analgesia via increased opioid activity and BLOCKING anaesthetic effects. This explains why Ketamine and PCP are both anaesthetic, while 3' substitutions of either aren't.
 
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Actually, after reviewing the links posted in this thread and after reading FnB's comments on the new compound, it seems pretty clear what gives K its affects:

- 2' halo (possibly only chloro) substitution on the phenyl ring
- a Ketone on the 2' position of the cyclohexyl
- (possibly necessarily a LACK of 3, or any other than 2', ring substitutions)
- (possibly, an N-substitution).

As such, I'd be interested in knowing your predictions (or maybe testing?) for SARs of the following:



And the other halogen analogues thereof.
 
Correct me if I'm wrong, but isn't norketamine simply de-methylated K? So The compound you refer to would simply be ethylketamine.
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No... The correct name is n-ethyl-norketamine (remove the methyl -> norketamine, replace with ethyl -> n-ethyl-norketamine.)

I would predict the fluorine analogue of ketamine to be something of interest. Replacing the chlorine with hydrogen makes it more potent but loses much of the ketamine quality. Fluorine is midway between hydrogen and chlorine, so possibly a fluorine analogue of ketamine could be more potent while retaining the ketamine quality of high.

As for the others...

The 3-meo might be interesting. One could assume it to have opioid activity. But then again there's no telling if the ketamine quality will be retained with such substitution. Probably not.

Although we will never know until someone makes them and tastes them ;)
 
^ Ah good point, thanks for the correction :)

re: compound "C" above, I put it there because I wonder, would several ring substitutions deminish the drug's effects (as is the case with some Tryptamines?) or bring out the best in both?

And while we're at it, I'll explain my main questions for posting the above compounds in particular. It is not really for "chemical masturbation" =D, but rather because they'd answer specific questions (for me, at least). Because as far as I'm concerned, Ketamine itself is as close to perfection as a drug can get... but n-Et-norket does sound promising if it is just like K but more potent.

But anyway:

A: I'd be surprised if this hasn't been synthed yet. One of the above mentions PCA (the non-ketone version of it) briefly, saying only that it is 1/2 the potency of PCP. What would adding the Keto group by itself do?

B: Simply an interest in other halogens, like what dread was talking about.

D: I'd be surprised if this hasn't been made and tested yet. Again, what would the keto group do to change PCP? Comparing this to PCP, the compound in "A" and Ketamine would probably give some good answers, as would it shed light on the important of the halogen.

E: A pretty obvious compound. I doubt a Piperidine ring would seriously change the effects of K.
 
Well, if I recall correctly, piperidine is less potent than methylamine. Could be wrong though... but with the already low potency of ketamine I wouldn't want to go lowering it any further.

I actually think a more potent analogue of ketamine would make loads of sense. It seems most of ketamines harmful side effects are due to the metabolite norketamine. Now if we have an analogue that is more potent ie. you need to take less of it then you will also get less of the nor-metabolite, and be healthier.

So 2-(2-fluorophenyl)-2-ethylamino-cyclohexanone (ketamine with cl -> f and me -> et) is something that should be made. If I had to guess I'd say it to be something like 2-4 times more potent than ket.
 
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