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PCP analogs (Cumulative) - Retrospective - Bioassays

(zonk)

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You have 3 different posts for 4-Methyl-PCP, one is just as if not more potent, one is inactive, and the other is less active.
 

Jamshyd

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Nice, but the apparent focus on potency over anything else was somewhat disappointing.

I would have liked to hear more of 2'-Chloro-PCP and N-Ethyl(nor)ketamine

You say 2'chloro-pcp is more "analgesic". In your observation, does the 2'-chloro group add *something* that is only present in Ketamine of all the ones mentioned?

I am trying to figure out if Ketamine is that out-of-this-world (no pun) unique in terms of SARs or if there is some kind of pattern, as I and several others seem to agree that simply sticking a 2-Keto group doesn't make a drug ketamine-like (methoxetamine and 2-keto-PCE both had more in common with PCP than they did with K).

But yeah, I really dream of trying (racemic - I really don't get people's obsession with S-isomers) N-Ethyl-norketamine one day, just to get another clue as to the above questions as it seems very few people understand just what this unique effect I am talking about is. I could really care less about potency, but then again I don't manufacture or drugs.

Other than that, Rolicyclidine appears very interesting. I'd love to try its 2'-Chloro-2-Keto analogue :).
 

Psiclo

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Silly question, but why are some of these more interesting chems (and from similar threads) available?
 

Jamshyd

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Actually the majority of the stuff in that list is NOT available and was probably only tried by one or two people ever. To my knowledge, I've actually never heard of anyone trying most of these until I read this post.

That said, there has been a LOT of talk about arylcyclohexamines for ages. It was inevitable that one or two of them might pop up.
 

planckunit

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You have 3 different posts for 4-Methyl-PCP, one is just as if not more potent, one is inactive, and the other is less active.
yeah, one is 4 methyl on the piperidine, the other one on the phenyl, the other one on the cyclohexyl ;)
 

(zonk)

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thanks for clearing that up, i feel stupid for not noticing it. That's real interesting about the cyclohexyl ring modification
 

(zonk)

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Is there any reason why this wouldn't work or hasn't been done? It would seem like it makes more sense in terms of bang for your buck.
Thienyl(tenocylidine)analogs
3-Methoxy-TCP
4-MEO-TCP
2-MeS-PCP(right???)
and then maybe the 2-oxo(ketamine) derivatives...
(sorry for doubleposting but this Q went nowhere in Advanced)

For 2-MeS/2-oxo-2-MeS, is this possible? to have the alkyl branch off the sulphor? Is it possible to have a Methoxy attached aswell?
 
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<pyridinyl_30>

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Also, will you consider sharing what you have more recently learned about opiates' structure activity relationship?
 

adder

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Concerning your first question, I've no data but this and 2-naphtyl may be easily put into one group with BTCP (GK-13, 2-naphtyl is GK-189). BTCP is devoid of NMDA blocking action so a similar compound wouldn't have been subject to those tests. With BTCP being an indirect dopamine agonist, 3-indolyl or 2-naphtyl are more anxiogenes than anything else. If I were to put something instead of phenyl group, the first one would be a 2-furanyl analog as it's the most logical step knowing TCP is stronger than PCP. There's still a number of not mentioned more complex analogs of PCP showing some action actually desired in this work that was anesthesia and analgesia.

And concerning your second question, I do post about opioids SARs in various threads, maybe PM me what you're concretely interested in so the discussion doesn't go off-topic here. But keep in mind all I am is a student of chemistry with no researches funded with unlimited money. ;)

I am trying to figure out if Ketamine is that out-of-this-world (no pun) unique in terms of SARs or if there is some kind of pattern, as I and several others seem to agree that simply sticking a 2-Keto group doesn't make a drug ketamine-like (methoxetamine and 2-keto-PCE both had more in common with PCP than they did with K).
2-oxo is not mandatory to have a dissociative anesthetic, that's clear. There's a simple explanation why such works are done with comparison to ketamine - since it's introduction in human use there was no drug manufactured to replace it so it's inevitable to include it as an example while searching for other anesthetics being phencyclidine analogs. Anyway, 2-oxo seems to be a key in augmenting sedative action as it's seen not only in ketamine but also in tiletamine. Actually, a substituent on orto position on phenyl ring in ketamine probably plays a bigger role in analgesia/anesthesia and 2-oxo is good to make suitable doses for use higher. It does its job in medicine.
 

SKL

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Very very very good read, about a class of compounds I've yet to explore in any real depth. Thank you
 

fastandbulbous

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Parke Davis stuck the keto group in there to shorten the half life by a considerable amount. It gives tha body a metabolic tab to start manipulating the molecule with an eye on getting it out of the body. PCP doesn't have that long a half life, but can be 'recycled' within the body, diffusing from the bladder back into the bloodstream, making the drug hang around longer than it's wanted. Stick a nice polar tag like a keto group somewhere and not only does the body have loads more ways of being able to metabolize the drug, but it reduces the fat solubility, so it can't re-enter the bloodstream from the bladder as well.

What has to be understood is that the shape the PCP molecule takes up in vivo, makes it a difficult metabolic target, which is why ketamine was developed - in fast (retains fat solubility, sort of), out fast (the keto group makes it easier to excrete) - once a drug is stopped being administered, you (from a medicinal/pharma point of view) want traces of it out of the body a.s.a.p. In terms of that, a hydroxyl group would be better because it allows conjugation with things, but in this case, a hydroxyl caused the potency to drop off the scale.


Basically, for other dissociative effects, play around with the aryl group (such as swap it for thiophene/other aromatic heterocycles or add ring substituents such as 2-chloro or 3-methoxy) or the amine group (sec or tert amine, heterocyclic/PCP or aliphatic/PCE), but playing around with the cyclohexyl ring either abolishes activity or leads to much more potent opioids, moving away from being a dissociative and potentially changing the whole nature of the final activity of the compound. BTCP was a case of modifying it so the DRI activity remained, but everything else dropped off (unfortunately it picked some new activities, like hepatotoxicity)
 
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(zonk)

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So for the non keto(ketamine)versions of PCP(2-MeO/2-chloro- PCP)u said the activity was diminished quite a bit. How did the activity compare to ketamine. Were the effects similar, were they more or less potent than ketamine and 4-meo-pcp?
 

crOOk

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omg adder, I just fell deeply in love with you!
 

adder

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@fastandbulbous

I totally agree, for anesthetic purposes there was clearly a need for some phencyclidine analog that would have a shorter action. 2-oxo will decrease any structure potency certainly and adding ketone anywhere else on the cyclohexane ring may even yield a chemical with no PCP activity (vide 4-oxo-PCP or 4-phenyl-4-(piperidin-1-yl)cyclohexanone but then again this one has analgesic effects so I still think 2-oxo does the same).

One thing I know for sure is 2-chloro on phenyl in ketamine increasing analgesic/sedative action and this may be substituted by methoxy group. I don't know how thiophenyl group substitutes here (ketamine vs. tiletamine, the second is also short acting and quite similar EDIT: just all keep in mind it's much less predictable dissociative) but sulfur atom may play a role there (comparing 3D images of ketamine and tiletamine). Anyway, I don't think I'm that experienced to state it's absolute truth. I really lacked access to payable assays and articles to summarize it all better.
 
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adder

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There have been some new works on adding -CF3 group to various compounds. The only "pain in the arse" is keeping in mind CF3(-) is unstable as an anion.

But what impact would it have on ketamine (chlorine substituted with trifluoromethyl)? Sure, it's hard to break down for human body so the expected outcome would be a longer acting compound with very much similar activity. I guess compounds like 2C-TFM or DOTFM are very scarce on the market because underground chemists have problems with protecting reactions with catalysts.
 

adder

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Right, this is what's it's all about. I'm very dubious concerning a ketamine analog with -CF3 instead of -Cl whether it would really be a stunning material or rather something to make money on. It's strongly connected to the purpose of chlorine presence in ketamine. With that carbonyl group being placed on cyclohexane ring generally for easing elimination and diminishing the time of the drug's action, o-chloro (and other substituents there?) probably alters analgesic activity more (N-ethylnorketamine vs. PCE is the best example: a hardcore dissociative and a relatively easy to handle chemical). Although I want to remind you that 4-oxo-PCP is active and is an analgesic with targets those of morphine but is devoid of action at PCP receptors. Knowing this, I'd risk a statement that 2-oxo adds something to analgesic profile of ketamine as well but sure from the view of big pharma it's great because it makes the compound easier to be metabolized.

With this knowledge I'd really want to see some concrete SAR work on orto position of phenyl ring more than significance of carbonyl groups attached here and there. o-chloro and o-methoxy - that's not enough. Would o-hydroxy be alright there also? Yes but would o-isopropyl be alright there as well (or just any substituent that's probable to cause different effect on molecule's neuropharmacology than chlorine).

I mean - is methoxetamine that good? Well, it's actually very different for me from ketamine or tiletamine, or PCP. But I guess someone makes good money off it. The same might happen with "triflometamine" or whatever. Anyway, it's doable for sure following the route used for making ketamine for black market but in theory that's not the only possible way.
 

leiphos

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I'm considering a couple hundred mgs 4-meo-pcp with 5-10mg 4-aco-dmt this evening... anyone have any thoughts or experiences on this?
 
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