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3-substituted PCP derivates

izo

izo

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hi,

i just stumbled upon what i think is an anomaly. 3meo-pce is more potent than 3meo-pcp but 3ho-pcp is more potent than 3ho-pce. didnt thought that the N alkyl subsitutent interchanges potency with these classes of compounds. also tried what i believe is 3cl-pcp. around 40mg rectally. it is almost not dissociating at this dose but makes me calm and almost feels a little serotonergic. possible that the electron withdrawing potential of the Cl on the 3 diminishes dissociating potential but then this is also the case with the OH group and these agents are clearly dissociating although nowhere as strong as the 3-methoxy compounds. any input or related papers about the effects of substituents on the 3 position of the arylcyclohexylamines?
 
had a proper dose of 3Cl-PCP by now. this stuff is disguisting, as bad as 2-fdck. dont know if 3F-PCP is similar. can anybody make a comparison about these two? 3meo-pcp was miles better. so anybody with experience of 3cl-pcp and 3f-pcp?
 
One thing I have found is that the degree of dissociation has a direct effect on fear and disgust. I first noticed that PCP directly reduced the sense of disgust. Even the thought of scat porn would leave me retching and having to concentrate to prevent vomiting. After 10mg of PCP hydrochloride, administered intramuscular, I found that the thought of said porn didn't make me retch, at all. I didn't go as far as watching any (fuck, I don't want those sort of images in my memory), but after the drug had worn off (48 hrs, to make sure), I found I could discuss it without the disgust. After trying other dissociative drugs (PCE, 3-MeOPCP & 3-MeOPCE), I found I had developed a sort of permanent immunity to disgust regarding that subject.
Also, dissociatives also seem to abolish knee jerk fear regarding spiders. I have touched big spiders under the influence (something unimaginable otherwise).
The combination of those two damping down of those two amygdala triggered responses can be learned, such that I am slowly desensitizing myself to arachnids (useful at this time of year). I'm pretty certain that these two decreased responses are responsible for the shock horror tales regarding these drugs (member of the Wu Tang Clan who cut off his dick and Big Lurch's bout of cannibalism).
Has anybody else found that dissociatives have reduced these two responses, that can really fuck up being able to function normally?
 
fastandbulbous said:
One thing I have found is that the degree of dissociation has a direct effect on fear and disgust. I first noticed that PCP directly reduced the sense of disgust. Even the thought of scat porn would leave me retching and having to concentrate to prevent vomiting. After 10mg of PCP hydrochloride, administered intramuscular, I found that the thought of said porn didn't make me retch, at all. I didn't go as far as watching any (fuck, I don't want those sort of images in my memory), but after the drug had worn off (48 hrs, to make sure), I found I could discuss it without the disgust. After trying other dissociative drugs (PCE, 3-MeOPCP & 3-MeOPCE), I found I had developed a sort of permanent immunity to disgust regarding that subject.
Also, dissociatives also seem to abolish knee jerk fear regarding spiders. I have touched big spiders under the influence (something unimaginable otherwise).
The combination of those two damping down of those two amygdala triggered responses can be learned, such that I am slowly desensitizing myself to arachnids (useful at this time of year). I'm pretty certain that these two decreased responses are responsible for the shock horror tales regarding these drugs (member of the Wu Tang Clan who cut off his dick and Big Lurch's bout of cannibalism).
Has anybody else found that dissociatives have reduced these two responses, that can really fuck up being able to function normally?
Click to expand...

Can't say this has happened to me. They can induce a lack of fear of bad behavior with regard to smashing things (though I haven't done so fortunately), but more out of a sort of psychotic akathisia/inner tension (whereby I feel restless and don't know what to do with myself, like a gorilla on too low of a dose of tiletamine)

What you are describing reminds me of how the NMDA agonist-antagonist d-cycloserine is used in exposure therapy to reduce fear of specific things, in this case, spiders:

pubmed.ncbi.nlm.nih.gov

The effect of D-cycloserine on subliminal cue exposure in spider fearful individuals - PubMed

Research on D-cycloserine (DCS) has demonstrated a significant effect on symptom reduction in human studies that utilized conventional exposure-based approaches. Recent studies have offered promising results for targeting fears through subliminal paradigms. In this double-blind, randomized...
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov

I can't say that's happened to me, although I suppose I've never tried to channel such an effect.
 
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I read about such compounds in 'The European Journal of Medicinal Chemistry'. The most potent of all wasK

ibb.co

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The paper did not cover N-monosubstituted analogues but the S altered binding between 2 different sites and had the lowest ED50 in test animals. It's ALL possible but when you discover that the above takes 12 steps, you realize it's also of no value.... unless we open a chain of high-class 'crushed herb' shops in the most affluent areas of Japan (places where people will pay $180 for 1 dose of 2CB).

I mean, those places ARE nice. REALLY comfortable places to sit, live DJ, lots of art, animated holograms and all manner of stuff to entertain the tripping and even free tea..... but then you think that with the rent costing $20000/month, these people have GOT to be making a huge profit.
 
Can't make out the name or structure of the lower molecule from the diagram or printed iupac name (reolution leaves a bit to be desired). Is the heteroatom in the cyclohexyl ring sulphur or oxygen. Thiophene is better, in terms ofED50, but tends to be a bit more of DRI.
 
It's a sulfur. As I said, it was in 'The European Journal of Medicinal Chemistry'. The synthesis is NOT trivial but it's interesting to understand QSAR.

Swapping the cyclohexane for a thiane would bypass the arylcyclohexylamine laws. I cannot remember which issue, but I'm sure given a day or two it's possible to find. An MXE homologue would, I'm sure, bu best of all.... but that would be VERY complex synthesis.

But it may be worth having some isophenidine homologues made. If an ortho -F or ortho -Cl on the A ring increase NMDA activity, a p-Me on the B ring will increase DRI (and lower duration). I never got the chance to try them all because commercial exigencies meant diphenidine & methoxyphenidine were made in bulk.

It is VERY annoying when you haven't finished your work to have someone else just decide 'goo enough;. One cannot be proud of 'good enough'.
 
ok, a little bit more work and nothing you can bring out for dirt cheap. so a little less profit margin. the real problem is that the market is controlled by greed and cheap drugs. nobody is in the game for the customers experience, so it looks to me.
the usual pharma spaddel still in control where things are going (wrong).
 
It's HARD chemistry. Most chemists simply hasn't the skill not the qeuipement. The yields are LOW. I mean, it has 2 chiral centres so 3/4 of your final compound (after 12 steps) gets throw away in any case.

J think it's in the region of 6%.

So the thiane homologue of 3-OH PCP is going to be hard enough as it is. That S precludes certain reactions, alters solubility and generally makes everything difficult.

I did find the specific issue and post it a while ago, but AFAIK nobody actually got the paper. I only remember it because I gave up - isophenidine derivatives were a much better area to research.

I'm in good company. Janssen gave up on the 3,3-diphenyl heptanone class of opioid and went with the phenylpiperidines. First phenoperidine then fentanyl. One has to make a call about when something just isn't worth the effort.
 
Almost everything is possible - but it it costs £2500/Kg, it's not going to sell. Don't forget MXE could be made on a K production line so the infrastructure was there.

Isophenidine costs £1000/Kg.

You have to be practical. That's why we don't see clandestine levorphanol on the street even though it ranks as one of the most euphoric opioids known. Even dextromoramide is considered too much work. In Russia dipipanone DID appear, but the 1 chemist making it found methadone was more profitable.
 
Check the cost of precursors, reagents and solvents. I even posted a link to the 1 step the synthesis involves. It's £1045 for 1Kf and goes down if you make in bulk. For a dose unit of 100mg.

THAT is why it's an interesting target. The 2-F and 2-Cl homologues have more NMDA activity & so adding a '2-Me will increase DRI activity to balance it. Yes, a novel precursor would be require but in bulk, it's still going to cost about the same per dose - and since that is 10p per dose, THAT is what is of interest.

It's like levorphanol analogues. An AMAZING target with some examples being x1100 M but it's also hugely synthetically complex to make which is why U-47700 was the choice. In the wider world where people don't follow the law, fentanyl is the cheapest opioid per unit. It's crap, plastic and short-acting BUT the market will accept it and so it's a success.

It's one thing to imagine a world where you look for new ligands, cost being immaterial. Quite different when it's all done to make money. Sorry, but that is the way of the world.

I should look at things like naloxone. Someone posted a 1 step route that yields noroxymorphone in almost 100% yield. Adding a phenylethyl (for example) yields something x80M. People are not doing this for fun - it's all business.
 
Fertile said:
It's HARD chemistry. Most chemists simply hasn't the skill not the qeuipement. The yields are LOW. I mean, it has 2 chiral centres so 3/4 of your final compound (after 12 steps) gets throw away in any case.

J think it's in the region of 6%.

So the thiane homologue of 3-OH PCP is going to be hard enough as it is. That S precludes certain reactions, alters solubility and generally makes everything difficult.

I did find the specific issue and post it a while ago, but AFAIK nobody actually got the paper. I only remember it because I gave up - isophenidine derivatives were a much better area to research.

I'm in good company. Janssen gave up on the 3,3-diphenyl heptanone class of opioid and went with the phenylpiperidines. First phenoperidine then fentanyl. One has to make a call about when something just isn't worth the effort.
Click to expand...
Just because Janssen gave up, doesn't mean they're not worthwhile. And besides, norphenadoxone is unscheduled everywhere, as far as I can see, and by all accounts, phenadoxone is just as euphoric as dipipanone.
Food for thought...
 
The methyl side-chain on the phenadoxone scaffold is required for activity, or it is in all related compounds. If memory serves, the active conformation sees the alkyls beyond the ketone offsetting the position of the N: which is why one isomer is active and one is not. A dextromoramide homologue with a piperidine in place of the morpholine was never tested AFAIK but it isn't controlled anywhere. Phenadoxone shows that the morpholine doesn't automatically confer higher activity.
 
Fertile said:
Phenadoxone shows that the morpholine doesn't automatically confer higher activity.
Click to expand...

are you aware of any psychoactive where a morpholine makes sense potency wise instead of the usual amine or amide functions? i have the feeling that the morpholine is a bit of a weak functional group at drug design...
 
Well I'm not sure. I've not come across any. I guess the morpholine will have slightly different solubility characteristics and so I'm guessing dextromoramide has the morpholine to make onset faster.

I've noted that propiram/phenapromide derivatives with 3,3-dimethyl substitution of the piperidine are much more potent but I think that it because of 'improved receptor recognition. I'm almost certain (based on the study of other classes of opioid) that one of the 3-monomethyl derivatives will be slightly more potent BUT the 3,3-dimethyl is achiral. 3,3-dimethyl prodine & 3,3-dimethyl fentanyl are more potent than the racemic 3-monomethyl versions.

ICI went the furthest by placing a 3-hydroxy-3-methyl derivative of fentanyl. That WAS a lot more potent, but the synthesis was tricky.
I do not understand why people aren't selling the 3,3-dimethyl derivative of ANPP. React with propanoic anhydride or similar and you have a potent fentanyl analogue...

But I totally disagree with the use of fentanyl anywhere outside the operating theatre. It's no safer than phenoperidine (the Janssen offering before fentanyl).

Sorry, went somewhat off topic. The easiest place to test morpholine would be to substitute the piperidine of diphenidine. That would tell you a lot.
 
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