PCP analogs (Cumulative) - Retrospective - Bioassays

[crOOk]

Well thanks a lot for those replies! Gonna go through it more thoroughly in a sec, I just got home.

Methoxetamine is a 3-methoxy and it is quite active. The methoxy-cl substitution on the 2nd position of the phenyl group wasn't accompanied by any major change in activity according to your notes on the ketamine analogue. I know this isn't saying the same goes for the 3rd position on the phenyl ring, but still... MXE is a 3-meo and it seems that no other chloro-methoxyl substitution have been performed for us to judge the effects.

Regarding the halogens. We should remember chlorine is the least bulky of them all. Then again, it is also the most electronegative, so intuition would point towards size being the primary issue here, not electronegativity. I'd have no idea about the target protein structures, but if I had means to display the exact amino acid sequences around the pcp binding site, maybe that would give us a clue why Cl and MeO seem to fit, but other halogens don't. Does anyone from the top of their head know the exact length of a Cl and a methoxy group. Ofc it depends to what moledcule they are binding, but assuming a plain benzol ring with a methoxy OR a chloro group. Which one would be longer and by how many Angstrom?

I have the greatest reverence for your experience and knowledge on this topic, but MXE just seems to disprove your statement. The dosage is far below that of ketamine for example as well. We should probably instead ask ourselves: What does ketamine have that makes it so damn weak (dosage wise) compared to all the other arylcyclohexylamines (don't you love that word)?

edit: oh man, i want some software to display proteins, one that allows me to position potential ligands, ideally one that can run for a few days to find binding sites by itself or predict changes in conformation on the basis of known ligands' effects. fucking anatomy doesnt leave time for shit. if anyone can point me into the right direction, id really really appreciate it!! (got acd/labs already, havent even checked it out. still would be cool if i could at least prepare the software before diving into this...)

edit2: just found a list on that acd site. gonna be a long road ahead it seems, i dont understand half of those descriptions :D
http://www.acdlabs.com/products/auto_int/int/


im also DESPERATELY looking for someone who has access to this journal:

http://www.ingentaconnect.com/content/1386-2073

My one lecturer told he can get me single articles through a friend, but I wanna browse through it... Does anyone have access and can hook me up? Shit I'll pay you for it, not sure how and with what, but I would. Just don't have the cash for a subscription, I'm still studying, living alone with a daughter who is with me 3 days per week. So permabroke.

 

[MattPsy]

Try Chimera.
PyMOL is ok, too, but I prefer Chimera.

Ketamine is way weaker than MXE mostly because it's N-methyl rather than ethyl, and ethyl is significantly stronger, as adder stated.

 

[skillet]

The Cl in ketamine is in a different position to the OMe in MXE, so you can't just think about size.

Chimera is great for protein preparation and visualisation, but if you want to dock stuff to a receptor you'll need something else too. Autodock vina with autodock tools is free and fairly easy to use, just follow a tutorial and you should be up and running pretty quickly.

Can't help you with the Bentham journals sorry, seems not many uni libraries bother to subscribe to them.

 

[adder]

^^^ did you actually test any 3-chloro's, or are you assuming?

No, I didn't test this one. This is an assumption based on a simple rule here. Bromo group and nitro group were placed at 3C during my wee research to test what effects, if any, 3-halo- and 3-pseudohalo- derivatives produce. Both groups are deactivating groups, that is electron withdrawing. All halogens, -NO2, -CF3, -CN, etc. will have the same effect there. Not to mention carboxylic acids, esters, etc. as these will have problems getting to brain. Unfortunately, my lab is all in cardboard boxes so I can't make a test just for the sake of seeing if my assumption is right for chlorine too (well, actually this is also found in literature, maybe if it was me I'd have got some grant ).

The methoxy-cl substitution on the 2nd position of the phenyl group wasn't accompanied by any major change in activity according to your notes on the ketamine analogue.

That's the point of SAR. It's a totally different thing comparing activity between compounds with substituents at 2C and 3C. Methoxy group may be similar to chloro group taking one thing into account and then again fall into a completely other group when analysing something else.

As for bond lengths these can be taken from tables found in chemistry textbooks:
For C―O it's 1.43Å and for C―Cl it's 1.77Å.

 

[crOOk]

Isn't C-O a carbonyl group? I was looking for MeO, so that'd be C-C-O. Plus I'm not sure if they're the same when attached to a benzol ring instead of a simple standalone carbon monoxide/formaldehyd or chloromethane molecule.

Btw, they are synthing that last k analogue commercially now, sigh... (the one with the meo substitution for cl)

 

[adder]

Commercially? I guess you mean RC scene. 2-methoxydeschloroketamine has no advantage as an anaesthetic over ketamine. I haven't heard about 2-methoxydeschloroketamine being marketed.

A carbonyl group is C=O and the length of this bond is 1.23Å. You wanted a bond length between carbon and oxygen in methoxy group, there's a single bond between them. -OCH3 isn't "C-C-O", you're counting in one carbon from the aromatic ring and it's all mixed up because then it's

   C==C         H
  /    \        |
 C      C---O---C--H
 \\    //       |
  C----C        H
 /
the rest of the structure

Of course I'm not saying all single carbon-oxygen bonds are the same and their length is ~1.43Å, it's different in e.g. carboxylic acids or epoxides.

 

[crOOk]

Ye ofc I mean the rc scene. Found a well known site (it's as legit as rc sites get lol) that claimed they'll have it stocked at the end of February. I'll neither buy any nor would I pass on the address for that purpose. Seems like PCP analogues will soon be flooding that market anyway... Enjoy it while it lasts. :/

I guess I had things mixed up, methoxy = -OCH3 though and not -CH2O, but nonetheless, doesn't length vary when being attached to an aromat like benzol ring vs., say an alkan like hexan?

edit: Ketamine seems to be in extremely high demand in a lot of places these days. Most German K seems to be pharm grade, not all from vials, but also stolen from pharmaceutical labs, since it isn't as strictly controlled that's much easier than stealing e.g. opioids for employees. Price has risen sharply, I paid like 10% of what people pay in the street retail market now or a lot of people gave it to me for free cause noone wanted it. Now it seems to be in constant demand, always available but never enough.

I guess some clever rc retailer figured out that he can easily sell a gram for a shitload of money and had the stuff synthed. I doubt it's supposed to pose any advantage over k, but instead just be very close to it. Especially with K being schedule III or whatever so that most analogue laws probably won't apply anywhere. You probably couldn't even call it a pcp analogue since it's obviously so close to a medication. In Germany anything that could ahve use as medication is illegal to possess without license.

 

[limonov]

This is my all time favourite thread and I have wanted to ressurect it for some time- Thank you to Adder for this, one of the best contributions to BL ever made, and thanks to Cr00k for taking the blame for any 'thread necromancy' allegations . Also, I'm not a chemist- the little knowledge I have comes from reading dozens of articles as well as mining BL and other such places for info, so I apologise for the inevitable moments of retardation on my part...

Anyway! Arylcyclohexylamines!

Your description of 4-Oxo-PCP being almost devoid of NDMA blockage effects, instead possessing more pronounced analgesic effects. Could this have the potential to be able to 'balance' the more manic/psychotic effects of a drug? For instance, 3-MeO-PCP is noted for causing manic episodes, as is 3-MeO-2-Oxo-PCE (MXE)- is there the possibility that 3-MeO-4-Oxo-PCP/3-MeO-4-Oxo-PCE would be less likely to cause manic episodes?

Additionally, Ketamine is 2-Chloro-2'-Oxo-PCM- what would the effect be if you were to subsitute the 2-Oxo for a 4-Oxo i.e. 2-Chloro-4-Oxo-PCM? Speaking of Ketamine- would there be the possibility of making a whole series of ketamine analogs, for instance: 2-Chloro-2'-Oxo-PCE (this is the 'Ethylketamine' you refer to, right?), 2-Chloro-2'-Oxo-PCP, 2-Chloro-2'-Oxo-PCPy, 2-Chloro-2'-Oxo-PCPr and so on?

Similiarly, Methoxetamine is 3-MeO-2-Oxo-PCE. I presume that there would be a whole series of analogs that could be derived from this pattern e.g. 3-MeO-2-Oxo-PCP, 3-MeO-2-Oxo-PCE, 3-MeO-2-Oxo-PCPy, 3-MeO-2-Oxo-PCPr, even 3-Meo-2-Oxo-PCM (which is closer to ketamine than MXE is).

Most of this is simply me broadcasting my dissociative wetdreams on the internet, however your description of 4-Methyl-PCP was intriguing. If it is a relatively straightforward PCP analog then surely it would be marketable as an RC- similiarly to how Amphetamine is illegal but 4-FA is sold as an RC. Would 4-Methyl-PCE or 4-Methyl-PCPy be more similar to their parent compounds (PCE/PCPy) or would they be more similiar to 4-Methyl-PCP (i.e. more like PCP than their parent compounds)?

I am interested in your opinions on 4-Meo-PCP. Its main drawback was its low potency, however it was a pleasant material- quite a laid back dissociative (you don't need to be balls-to-the-wall all the time). I wonder if there would be any possibility of improving 4-Meo-PCP by tweaking it further- 4-Meo-PCE? 4-Meo-2-Oxo-PCP/PCE? 4-Meo-4'-Oxo-PCP? Although the 4-MeO results in diminished potency the material itself is worthwhile- prehaps further manipulation could yield interesting effects with a potency similiar to ketamine?

And finally, what may be the stupidest question...wouldd it be possible to substitute the 2-chloro group on ketamine for other groups e.g. 2-Bromo-2'Oxo-PCM or 2-Iodo-2'Oxo-PCM (ala Pikhal)? Would this result in any difference in effect? Even minor variations on Ketamine could be both interesting and enjoyable. You also mention that '2-chloro compounds give something more to the analgesic effects'- could something along the lines of 2-Chloro-4-Oxo-PCE provide some sort of interesting dissociative analgesic?

 

[adder]

doesn't length vary when being attached to an aromat like benzol ring vs., say an alkan like hexan?

The very same bond can have different lengths but this is not the case here. Besides carbon from methoxy group isn't bond to the aromatic ring, it is bond to oxygen.

Your description of 4-Oxo-PCP being almost devoid of NDMA blockage effects, instead possessing more pronounced analgesic effects. Could this have the potential to be able to 'balance' the more manic/psychotic effects of a drug? For instance, 3-MeO-PCP is noted for causing manic episodes, as is 3-MeO-2-Oxo-PCE (MXE)- is there the possibility that 3-MeO-4-Oxo-PCP/3-MeO-4-Oxo-PCE would be less likely to cause manic episodes?

No idea. I haven't really tested 4-oxo-PCP like a guinea pig to know if it causes manic episodes. Also, 4-oxo-PCP is not totally devoid of PCP properties ("almost"). It's just that analgesic effects totally overwhelm dissociative effects.

Additionally, Ketamine is 2-Chloro-2'-Oxo-PCM- what would the effect be if you were to subsitute the 2-Oxo for a 4-Oxo i.e. 2-Chloro-4-Oxo-PCM? Speaking of Ketamine- would there be the possibility of making a whole series of ketamine analogs, for instance: 2-Chloro-2'-Oxo-PCE (this is the 'Ethylketamine' you refer to, right?), 2-Chloro-2'-Oxo-PCP, 2-Chloro-2'-Oxo-PCPy, 2-Chloro-2'-Oxo-PCPr and so on?

Similiarly, Methoxetamine is 3-MeO-2-Oxo-PCE. I presume that there would be a whole series of analogs that could be derived from this pattern e.g. 3-MeO-2-Oxo-PCP, 3-MeO-2-Oxo-PCE, 3-MeO-2-Oxo-PCPy, 3-MeO-2-Oxo-PCPr, even 3-Meo-2-Oxo-PCM (which is closer to ketamine than MXE is).

Sure it is possible to synthesize many ketamine/methoxetamine analogues, it's just a matter of changing the synthesis routes. But you have to mind changes in activity and effects. Moving carbonyl group from position 2 to position 4 could abolish ketamine "magic", i.e. the balance of dissociative effects and analgesic effects would change, lengthening N-alkyl chain would abolish activity, the longest/bulkiest passable would be propyl/isopropyl.

Now this is just speculation. If I were to move "=O" from 2 to 4, I would add methyl group at 2 because it's known to boost activity. Anyway, I've got no idea what effects the compound would have.

Would 4-Methyl-PCE or 4-Methyl-PCPy be more similar to their parent compounds (PCE/PCPy) or would they be more similiar to 4-Methyl-PCP (i.e. more like PCP than their parent compounds)?

4-methyl on cyclohexane ring is a boost for activity at the PCP receptor.

I am interested in your opinions on 4-Meo-PCP. Its main drawback was its low potency, however it was a pleasant material- quite a laid back dissociative (you don't need to be balls-to-the-wall all the time). I wonder if there would be any possibility of improving 4-Meo-PCP by tweaking it further- 4-Meo-PCE? 4-Meo-2-Oxo-PCP/PCE? 4-Meo-4'-Oxo-PCP? Although the 4-MeO results in diminished potency the material itself is worthwhile- prehaps further manipulation could yield interesting effects with a potency similiar to ketamine?

The main role of 2-carbonyl group in ketamine is facilitating metabolism of the compound, so the duration of action is not as long as PCP for example. PCE is like 1.5 times as strong as PCP so it's not a massive boost in potency. It's not always that you can take a compound and make it stronger (I mean weight) by changing something in/adding something to the structure without changing effects (that being a result of changing affinities at different sites). E.g. you want a stronger morphine, so you synthesize N-phenethylnormorphine because you know phenylethyl boosts potency. But then again the latter compound isn't the same in feeling as the former compound.

wouldd it be possible to substitute the 2-chloro group on ketamine for other groups e.g. 2-Bromo-2'Oxo-PCM or 2-Iodo-2'Oxo-PCM (ala Pikhal)?

No idea. Methoxy groups isn't as big as bromine atom or iodine atom so it fits in there without really changing the effects much.

could something along the lines of 2-Chloro-4-Oxo-PCE provide some sort of interesting dissociative analgesic?

It would abolish dissociative effects at all.

I don't have access to online libraries of articles any more because I finished my chemistry studies so I won't be able to answer all more complex questions. Also, I don't have as much spare time as I used to because being a chemist turned out not to be a good thing for earning money so I had to take up a few courses to go back to England and take up different field of study.

 

[crOOk]

What are you studying now adder?

 

[adder]

Computer science + taking a few courses for warehouse work and renovations like driving a forklift, welding, and tiling at the moment.

 

[(zonk)]

Hey Adder, was hoping you could tell me more about 4-hydroxy-pcp, with all the 4-meo-pcp going around these days I figure this would be a breeze to make. I'm interested in trying, you said potency was like that of PCP but effects are different, can you tell me how different and in what ways?

 

[adder]

In short, an easier to control version of PCP, kind of more tranquil and less unpredictable but anyway puts some weight on the body, a dissociative through and through. Well, you'd imagine 4-MeO-PCP is metabolized to 4-HO-PCP as body will always want to clean such groups to -OH so the metabolite is more water-soluble. Anyway, I can't really go on about my personal feelings as I took it not more than twice. I wasn't really fond of analogues with anything on position 4.

 

[gladiolus]

Not a PCP anlog like the others mentioned here, but talking about dizocilpine - a very powerful NMDA antagonist, aka MK-801, one would imagine placing an =O on the available carbon could make it a much more useable substance in terms of shorter half-life, enabling those sweeter higher doses without extending the trip into the 2-day territory.

It seems the obvious choice for extending the half life of Ketamine would be 2'-chloro PCM. Am I right that no-one has mentioned this in this thread yet? (de-oxy version of ketamine).
keto-PCE looks like it might be interesting too. (the de-3meo version of MXE)

 

[Ligaturd]

Hey so, I recently found out about 3-ho-PCE's existence. I can't find anything on the net about it except people like my self looking for information. Looking at how potent 3-ho-PCP is, can i extract some sort of approximate dosage for this compound? Can anybody speculate about the effects it might produce compared to other substances that are similar?

 

[sekio]

PCE is 1.5-2x more potent than PCP, is it not? So go real fucking easy with that compound.

The 3-HO compounds are probably all active at <1mg. They are expected to be strong opioids, or at least have strong respiratory depressant action. Go really easy.

 

[redeyesmj]

Thanks for that info sekio,

 

[Transcendence]

So let me get this straight: you synthesized all of these yourself? You were 20 when you made this post, and you say these are from your old notes, so you synthesized all of these as a teenager? Not doubting you, just making sure I understand correctly because I'm really impressed.

 

[adder]

Not alone of course, and by old I didn't mean "a few years ago". I already studied chemistry by then + had my own group of people interested in chemistry like me and with one I also shared a small private lab. The guy had also studied chemistry, he just got expelled from the university in the other city... Well, it's a long story and it's not like we were focused on PCP analogues. As long as I stayed in the opioid addiction, I mean before I started doing methadone last time and didn't go back to i.v.'ing anything, it worked somehow. Now all the stuff is packed and waiting for a never coming buyer 'cause there's hardly a way to divide it, besides a lot of equipment were also not bought from the shop so it was already used. Anyway, I quit morphine and levorphanol, and nothing could make me work because I had to, I did it because I wanted to but eventually one runs out of reagents and stuff and it has to be closed down.

Really, it's a shame I can't find much time for chemistry in practice nowadays just because it doesn't really pay off to work as a chemist because of the low salary for a lot of effort...

 

[Transcendence]

That sounds like it could be a good book someday.

Really, it's a shame I can't find much time for chemistry in practice nowadays just because it doesn't really pay off to work as a chemist because of the low salary for a lot of effort...

Yeah tell me about it. That's why I decided not to continue on into grad school. I think you have the right idea with comp sci. and welding. Kind of wish I went with EE or a trade instead.