"Legal" RC synthetic opiods?

[4DQSAR]

Hey now, they must just have a hell of a recipe that allows for a super high return rate

I believe one was stated as having similar potency to carfentanil. BUT it mediates it's analgesic activity though KOP as well as MOP and KOP ligands produce dysphoria which is whe they aren't used medically. Yes, morphine DOES bind at MOP, DOP and KOP (and I wouldn't be surprised if it has NOP affinity). But importantly the balance means MOST of the activity is mediated by MOP.

The general term for opioids that act at two different classes of opioid receptors are 'dualists' but the only one used medically was pentazocine (AFAIK) and even then, the product was a racemate with one optical isomer acting primarily on the KOP receptor, the other at the MOP receptor.

Phenazocine demonstrated that modification could increase potency enough to make the KOP activity less of an issue.

 

[Rectify]

SMACK_DOWN
1-(3,4-diacetoxyphenyl)-1-carbomethoxy-2-methylaminopropane

 

[Rectify]

THE_VAMPIRE_LESTAT
(5R,9R,13S,14S)-4,5-Epoxy-14-carbomethoxy-3-methoxy-17-methylmorphinan-6-one

From oxycodone via The Andersen Sequence.

R-OH --> R-Cl --> R-CN --> R-(C=O)-OH --> R-(C=O)-O-CH3

 

[4DQSAR]

Sorry, I stand corrected. Phenazocine is (S) enantiomer so in fact almost all of the KOR activity was suppressed.

In fact it seems phenazocine was patented before pentazocine so one assumes researchers at Aventis read rhe earlier work by Smith, Kleine and French and what the latter considered a 'flaw', became a 'feature'. Serendipity is far more common than people suppose.

Just so people get what KOR ligands do - Salvia is a selective KOR agonist. I have never tasted pentazocine but even if it's only a partial agonist at the KOR, it does not sound nice which I assume was the 'feature'. But decades of dualist have come down the pike and been abandoned. The problem is that unless one can contact the researchers AND they are open to questions, knowing why a ligand never became a candidate is unknowable.

But a warm water tail withdrawal test carried out on a cohort of mice is sketchy at best in even approximating analgesic activity in man. Also, a white mouse cannot squeak about hallucinations and how awful it feels. So don't base your entire stratergy on locating the ligand that is simply the most potent. Chances are it will be terrible.

 

[TheLightBringer]

Sorry, I stand corrected. Phenazocine is (S) enantiomer so in fact almost all of the KOR activity was suppressed.

In fact it seems phenazocine was patented before pentazocine so one assumes researchers at Aventis read rhe earlier work by Smith, Kleine and French and what the latter considered a 'flaw', became a 'feature'. Serendipity is far more common than people suppose.

Was reading on benzomorphans today and just remembered your post, and a post from nicomorphinist from years ago:

This happened even more so with phenazocine, four times as strong as pentazocine, and dezocine, maybe 50 per cent stronger. The tripelennamine and phenazocine was the most euphoric and analgesic of the three mixtures.

Makes me really curious as to why pentazocine was chosen over phenazocine. Phenazocine according to its wikipedia article also doesnt cause spasm of the sphincter of Oddi making it even more worthwhile as a compound. A more potent, longer lasting and less dysphoric compound that doesnt cause SoO problems?

The R-isomer was 20x morphine while S-isomer was 4x morphine, now if the R-isomer has K-opioid agonism significant enough to cause dysphoria thats a shame but the S-isomer should still show promise

 

[4DQSAR]

@TheLightBringer - I admit I did not read about it to quite that level when I posted. I just recalled how the two were so structurally similar BUT what the origital researchers saw as a bug, others saw as a feature. It's important to remember this all took place in the 1950s and 1960s so benzomorphans must have been a LOT of work for synthetic chemists. It's a scaffold that flatters 3DQSAR analysis.

We have seen this elsewhere. If you read about viminol (Viminolo) the same lie is repeated in which one stereoisomer is a potent agonist, another a potent antagonists (the other four being inactive). But it turned out that the 'antagonist' enantiomer wasn't... but it made rats jump and how fast a rat jumps was used to assess opioid activity in animal models until the early 1990s. Now I think the people who made Viminolo know the truth but if they can sell it as a safer 'mixed aginist' then that's only going to increase sales. Proven to be untrue, still believed by most pharmacists.

 

[TheLightBringer]

@TheLightBringer - I admit I did not read about it to quite that level when I posted. I just recalled how the two were so structurally similar BUT what the origital researchers saw as a bug, others saw as a feature. It's important to remember this all took place in the 1950s and 1960s so benzomorphans must have been a LOT of work for synthetic chemists. It's a scaffold that flatters 3DQSAR analysis.

We have seen this elsewhere. If you read about viminol (Viminolo) the same lie is repeated in which one stereoisomer is a potent agonist, another a potent antagonists (the other four being inactive). But it turned out that the 'antagonist' enantiomer wasn't... but it made rats jump and how fast a rat jumps was used to assess opioid activity in animal models until the early 1990s. Now I think the people who made Viminolo know the truth but if they can sell it as a safer 'mixed aginist' then that's only going to increase sales. Proven to be untrue, still believed by most pharmacists.

Viminol is another interesting one, people in brazil are taking it with CYP3A4 inhibitors like ketoconazole and getting high as shit. I wonder what else can be done with the scaffold, the pyrrolidone derivative of Viminol called Z4349 is a whopping 318x Morphine Surely more compounds can be made using this as a base, I know 2F-Viminol and TFM and TFE Viminol didnt really take off, makes me wonder do we really want 100x and over potency compounds though? Will this be fentanyl and nitazenes all over?

Z4349 - Wikipedia

en.wikipedia.org

 

[4DQSAR]

Z4329 is not a facile target. But the work of Franco Conti demonstrates incremental improvement on optical synthesis & resolution of viminol (and it's homologues) couple potentially produce something around 7.5x M. Now that is a synthesis that really has been telescoped although ClCH2CN is a but shady but go all of that way and discover the product isn't up to much..

A rational person would obtain viminol and resolve that first, but the few people who mentioned raecemic viminol as being 'OK for pain' and nothing more.

 

[TheLightBringer]

Z4329 is not a facile target. But the work of Franco Conti demonstrates incremental improvement on optical synthesis & resolution of viminol (and it's homologues) couple potentially produce something around 7.5x M. Now that is a synthesis that really has been telescoped although ClCH2CN is a but shady but go all of that way and discover the product isn't up to much..

A rational person would obtain viminol and resolve that first, but the few people who mentioned raecemic viminol as being 'OK for pain' and nothing more.

Not sure if I misunderstood, youre saying there is a viminol derivative with 7,5x morphine?


I was thinking more about playing around with the 2nd position on the benzene ring like 2F-viminol just swaps the Cl for a Fluorine, instead doing so on the pyrrolidone derivative is sure to retain similar activity. We can assume the TFM and TFE derivatives will be active as well like they were on viminol.

 

[4DQSAR]

@TheLightBringer - no, their is one stereoisomer (of the six) that is around x5.5M as an analgesic in animal models. The flaw I was highlighting is that for decades the same paper would assign another stereoisomer antagonist activity thus viminol is a mixed agonist/antagonist. But as I pointed out, the way withdrawal was being detected wasn't reliable. AWS in rats was measured by how frequently they jump. It turned out the viminol isomer merely happened to make rodents dance. Someone actually obtained affinity data and only one of the six had a significant affinity.

But it's hard for me to believe the original makers didn't know, but I suggest selling it as as 'mixed agonist/antagonist' is how Viminol got it's licence in Argentina.

 

[TheLightBringer]

@TheLightBringer - no, their is one stereoisomer (of the six) that is around x5.5M as an analgesic in animal models. The flaw I was highlighting is that for decades the same paper would assign another stereoisomer antagonist activity thus viminol is a mixed agonist/antagonist. But as I pointed out, the way withdrawal was being detected wasn't reliable. AWS in rats was measured by how frequently they jump. It turned out the viminol isomer merely happened to make rodents dance. Someone actually obtained affinity data and only one of the six had a significant affinity.

But it's hard for me to believe the original makers didn't know, but I suggest selling it as as 'mixed agonist/antagonist' is how Viminol got it's licence in Argentina.

Ohh now I get it, thx for clearing up

Btw what would the scaffold/family/ligand of viminol like compounds be the closest to? I want to say at first sight they look like a distant cousin of thiambutenes but I know thats wrong. ”α-pyrryl-2-aminoethanol” derivative according to wikipedia. Its a class of its own I guess

 

[4DQSAR]

@TheLightBringer - Viminol is a little bit of a novelty becuase it makes use of chiral N-alkylation i.e. R,R , R,S, S,S-diescbutyl. So that's three stereoisomers but that secondary hydroxyl is also chiral also demonstrating either R or S isomerism. Making a total of six.

Now given that the medicine Dividol (raecemic viminol) was a a [P] medication in Argentina for decades without it seemingly becoming a serious social issue, I'm going to go ahead and suggest that it isn't likely to be any fun. Now Zambon and Witefin Holdings did explore the QSAR widely with Z4329 as the member of the series to show the most potent analgesic activity based on how fast mice withdraw their tails from warm water...

It's not nothing, but it's not a convenient synthesis, and I don't see it being telescoped. It's brilliant work but more rightly belongs in what I believe is termed 'exquisite science'.

 

[4DQSAR]

Oh, by the way, the MOST visible example of a class of opioid that originally began as a safer replacement for phenoperidine. Sublimize AKA fentanyl citrate AKA the prototype of the anilidopiperidine class of opioid.

I'm sure many people have taken a good look at the QSAR of the class as there really are thousands of potential ligands. But notice examples in which the B-ring was swapped from a benzene ring to a 2-thiophene (many, many papers cover that modification) and latterly examples in which many, many 5 and 6-membered rings were tested and some of them demonstrated analgesic activity far higher than the protoytype. But as far as I can tell, these did not end up on the street. The only example of a thiofentanyl homologue turn up was raecemic beta hydroxy thiofentanyl. That happened in St. Petersburg around 1996 and it killled hundreds.

I do not know but strongly suspect that ring with 2 heteroatoms (HBAs) may prefertentially bind to KOP. Yes, they also ring-fill but not as selective. So within one scaffold we are able to apply rational design and see a prototype that is quite selective to derivatives whose increased analgesic activity is due to it being LESS selective.

Still makes me laugh that George Marquardt failed to admit that having been an active methamphetamine chemist, he had ready access to BMK (benzyl methyl ketone) and in the telecoped synthetis of fentanyl homologues, one adds phenyl acetaldehyde for fentanyl and (wait for it) BMK to make αMF. Now the fact αMT has a significantly longer duration of action than αMF was almost certinly another good reason but Even when GM was making them, he ccould form and isolate the intermediate imine and that then offers multiple methodologies to reduce said imine to amine.

In fact GM had a theory that propanoic anhydride was 'watched' necause he theorized that a much simpler and much safer synthesis of LSD somehow made use of it. Now the reason was far more straightforward. A few years Before αMF, othrt clandestine chemists had noted that MPPP was an order of magnitude more potent than it's parenr (pethidine) and uncontrolled in what became known as 'The Case of the Frozen Addicts'



But to admit that would be admission that GM wasn't the first and indeed wasn't even the first in the US to produce 'designer opioids'. I have no doubt George Mardquandt was an extremely intelligent induvidual but serendipity was surely a major factor. I embrace it because I too have benefitted do KNOW we find stuff ny accident.

Sorry to reitterate this but affinity ≠ activity. I have seen multiple examples in which the lowest ED50 wasn't the compoud with the highest activity. Schmidhammer produced N-2-phenylethyl noroxymorphone which by almost every metric should be around an order of potency more potent than the prototype but in spite of the higher Ki, the EC50 was only marginally higher than the parent. So of no medicinal value

 

[4DQSAR]

I also feel it worth noting that there are homologues of anilinopiperidine (fentanyl class), ampromide (phenapromide class) and others in which the A-ring is swapped from a (ring substituted) benzene to an otho pyridine ring. The same modification is demonstrated by oliceridine (Olinvyk).

I've previously stated my hypothesis as that 'to demonstrate antagonist activity, the A-ring of the opioid must bear a meta phenol moiety or isobiostere thereof.' I had to expand the definition after I noted that 8-CAC shows an amide acting as a (long acting) bioisostere and that those examples with a pyridine moiety also demonstrated partial agonism.

I am always for that which helps people but it seems that for seven decades researchers have tried to design better analgesics. Partial agonists. But I wonder if genetic diversity means a medicine could work very well for one person and not at all for another. In the UK a duallist called butorphanol (Stadol). It was noted quite quickly that the medication was far more effective in treating severe visceral pain in women than in men.

My point being, I don't think their is a well established way to measure how partial a ligand is. Given that affinity is not a guide to effacacy, other than quite crude animal models, the subjective effects in man can only be demonstrated in one way.

Many years ago I talked to a guy in Paris who was prescribed and was injecting Suboxone. I asked if the naloxone doesn't send him into a massive rattle. His response was that he felt odd for a couple of minutes then fine. So for him, buprenorphine had greater affinity than naloxone. Now that's a single case report. No statistical value, I just thought it worth mentioning.

 

[MedicinalUser247]

Well... You can always resort to the old Loperamide with Alcohol trick. It depresses the central nervous system and causes euphoria when there mixed together.

 

[Opana313]

Well... You can always resort to the old Loperamide with Alcohol trick. It depresses the central nervous system and causes euphoria when there mixed together.

Eesh no Bueno

 

[4DQSAR]

Well... You can always resort to the old Loperamide with Alcohol trick. It depresses the central nervous system and causes euphoria when there mixed together.

Ahh, that 'old trick' that kiilled people.

Loperamide is actively transported out out the brain by P-gp until the sheer amount of lopermide overcomes that active transport and very bad things happen. There are quite a dew forensic papers on that particular trick.

What a lot of people miss is that norbuprenorphine is also actively transported out of the brain using the same P-gp which is a good thing since norbutorphanol produces the more classic activity demonstrated by a full agonist i.e. people pull a blue.

 

[4DQSAR]

BTW I also noted some 1,3,8-triazaspiro(4.5)decan-4-one class opioids turning up. There are any number of papers demonstrating how NOP selective the class is. Again, before the different types of opiate receptor had even been identified, Janssen had patented the prototype which in animal models demonstrated analgesic activity 400-450x morphine. But I know of at least three groups who one assumes had access to that unusual precursor and decided to try it out. Now who knows why, but not one of them appeared to ever release an RC based on that scaffold.

Later parents do demonstrate examples with both MOP and NOP activity but if momory serves, it was far more active at NOP. So in a way I suppose one could term it a 'dualist'.

 

[TheLightBringer]

BTW I also noted some 1,3,8-triazaspiro(4.5)decan-4-one class opioids turning up. There are any number of papers demonstrating how NOP selective the class is.

Same class as all the spiro- -orphine opioids that have been around lately? The reviews on them seem very mixed, mostly neutral to bad. Ive also seen Etodezitramide pop up recently, the bezitramide analogs seem like a better alternative to the fent and zenes due to much longer duration and less potency.

 

[TheLightBringer]

Id say the best alternatives available right now for people that dont want to blow their receptors with a sawed off Opioid-Shotgun would be DPP26 or IC-26, id compare those more to a small handgun to your receptors. Beware off potential cardiotoxicity with these ones though