Novel Opioids

[TheLightBringer]

2-aminoindane fentalog.

Damn I wonder if youre the first to think of that, I bet it would have some form of activity.


I remember thinking about a Bucinnazine/AP-237 and Fentanyl fusion molecule
”N-Cinnamyl-butyryl-norfentanyl”

Instead of the N-phenethyl on fentanyl there is an N-cinnamyl substitution like on AP-237, and the propionyl on the propanamide is extended by another carbon resulting in a butyryl group

Although Im sure it would be quite weak if active, yours is a better idea for sure

 

[TheLightBringer]

The Fent/Bucinnazine molecule would look something like this I guess…
(I seriously doubt it would have any significant activity though)


I know it looks off, dont shoot me, drawing in swisstargetprediction is hard with my shaky fingers

Im sure just having a cinnamyl group on regular fentanyl ie with the propionyl group would be a better canditate for an active molecule though

 

[Smyth2]

I found a strong Nazi analgetic but I don't know if it is opioid or not. These are the patents:

[1] Scheuing Georg & Walach Bruno, US2352020 (1944 to Individual).
[2] Dr Georg Scheuing & Dr Bruno Walach, DE728103 (1942 to CH Boehringer Sohn AG and Co KG).

 

[TheLightBringer]

I found a strong Nazi analgetic but I don't know if it is opioid or not. These are the patents:

[1] Scheuing Georg & Walach Bruno, US2352020 (1944 to Individual).
[2] Dr Georg Scheuing & Dr Bruno Walach, DE728103 (1942 to CH Boehringer Sohn AG and Co KG).

Theres just not enough info in those patents other than it acts as an analgesic. Theres likely a good reason it was abandoned, I would look through similar molecules and see if they have any documented activity

PubChem

PubChem is the world's largest collection of freely accessible chemical information. Search chemicals by name, molecular formula, structure, and other identifiers. Find chemical and physical properties, biological activities, safety and toxicity information, patents, literature citations and more.

pubchem.ncbi.nlm.nih.gov

Although interestingly enough swiss target prediction (which should largely be taken with a grain of salt but can be a good pointer) says that the most likely targets in order would be:
Serotonin, D4, D2, D3, nAchr-a4/b2, Kappa Opioid receptor, nAchr-a7, Sigma Opioid, Delta Opioid, NMDA subunit epsilon 2 and finally Mu-Opioid… (followed by a few others). https://www.swisstargetprediction.ch/result.php?job=86658635&organism=Homo_sapiens

It likely exerts its analgesic activity through one or more of the aforementioned receptors but we got no clue what kind of activity it really has…

 

[4DQSAR]

Theres just not enough info in those patents other than it acts as an analgesic. Theres likely a good reason it was abandoned, I would look through similar molecules and see if they have any documented activity

PubChem

PubChem is the world's largest collection of freely accessible chemical information. Search chemicals by name, molecular formula, structure, and other identifiers. Find chemical and physical properties, biological activities, safety and toxicity information, patents, literature citations and more.

pubchem.ncbi.nlm.nih.gov

Although interestingly enough swiss target prediction (which should largely be taken with a grain of salt but can be a good pointer) says that the most likely targets in order would be:
Serotonin, D4, D2, D3, nAchr-a4/b2, Kappa Opioid receptor, nAchr-a7, Sigma Opioid, Delta Opioid, NMDA subunit epsilon 2 and finally Mu-Opioid… (followed by a few others). https://www.swisstargetprediction.ch/result.php?job=86658635&organism=Homo_sapiens

It likely exerts its analgesic activity through one or more of the aforementioned receptors but we got no clue what kind of activity it really has…

Well, to be fair to the amount of about of work went into dezocine and related 6-alkoxy ligands. Dezodine only appears to be used in China so if a heartwarming story tells you hove a magic powder will halt EWS, chances are that was in China. But I'm still unsure if this is something around hydrocodone in terms of analgesic activity thus someone with a big fentanyl problem might need to at least have expectations and what are reasonable expectations.

If nothing else, low and slow. But the fact that two legal seeming biased ligands have been tested just to check if they are able to produce euphoria is, I suggest, something important to know.

For what it's worth, I still think that Fastandbulbous noted that at least two Enkephalinase inhibitors i.e. these are not inthemselves 'drugs'. what they do is to stop the body breaking down ligands or receptors (it slows down metabolism).

Now I really have no idea if it IS the better option but I suggest that clinicians follow histrionics as a LOT of money was thrown at the problem.

Again, no idea if it's true but fastandbulbous noted that there were several ligandslike those enkephalinase inhibitor (But imagine likely most have known ligands).

I do NOT think it will make you feel great but on the basis of slow and low with the absolute effects of the ligand KNOWN has got to be better than randomly guessing. I know it seems dumb but even know I will still always what medications a person is on if I give them a paracetamol. If It's someone trusting me with their health, that is a huge responsibility.

 

[TheLightBringer]

Well, to be fair to the amount of about of work went into dezocine and related 6-alkoxy ligands. Dezodine only appears to be used in China so if a heartwarming story tells you hove a magic powder will halt EWS, chances are that was in China. But I'm still unsure if this is something around hydrocodone in terms of analgesic activity thus someone with a big fentanyl problem might need to at least have expectations and what are reasonable expectations.

If nothing else, low and slow. But the fact that two legal seeming biased ligands have been tested just to check if they are able to produce euphoria is, I suggest, something important to know.

For what it's worth, I still think that Fastandbulbous noted that at least two Enkephalinase inhibitors i.e. these are not inthemselves 'drugs'. what they do is to stop the body breaking down ligands or receptors (it slows down metabolism).

Now I really have no idea if it IS the better option but I suggest that clinicians follow histrionics as a LOT of money was thrown at the problem.

Again, no idea if it's true but fastandbulbous noted that there were several ligandslike those enkephalinase inhibitor (But imagine likely most have known ligands).

I do NOT think it will make you feel great but on the basis of slow and low with the absolute effects of the ligand KNOWN has got to be better than randomly guessing. I know it seems dumb but even know I will still always what medications a person is on if I give them a paracetamol. If It's someone trusting me with their health, that is a huge responsibility.

Brother sometimes I love your posts and comprehend what youre saying, other times words seem jumbled, in the wrong order or out of context. I understood the first half contextually.


Still love your posts though not trying to sound like a dick just wondering if theres a language barrier

 

[4DQSAR]

n hosted at ImgBB

Image n hosted on ImgBB

ibb.co

Wilson and Pircio, Nature (London) 206, 1151 (1965).

This work is also covered by CA Patent 830475A 'Analgesic cyclobutanes derivative compositions'

I can only apologize. I had eight years of my life in which an 'short message from the editor' or whatever this is the digital version of, I fear I was driven into writing in a manner that precludes misunderstanding.

I use ChemSketch and PubChem for lazy stuff, I break out the toys for work.

BTW Why not try overlaying the product with 2,2-Dimethyl-3-methylamino-N-phenethyl-3-phenyl-propionamide.

As to that latter compound. First some basic housekeeping, yes, there were enough examples so quickly that the single active isomer was located. The secondary methylamine proved to be the most active. Now, as I have suggested before, an that extra moiety is why it's behaviour is so unusual.

As we will also learn, what kind of dipshit am I. The paper liked to mix and match µm and nm.

Well, OK, I'm feeling a bit keen since simply by using a simple training set, a large set that included several widely prescribed opioids. But the paper's title even specifies 'antagonists' and what you and I both know but that seemingly we are the only two? Yep - for an opioid to demonstrate ANTAGONIST activity, it must contain a phenol or bioisostere thereof.

Now I had mis-read that Ki as being 0.1 mmol... although in my defence, that paper did that for them ALL. So my candidate as having some 1000 times LESS affinity. But that's fine, I just want all the agonism and take it. After swearing and complainin we finally did some animal models. As far as we can tell, it's around x10 oxymorphone and can be made in two steps (the lack of the phenol makining it far easier).

Honestly, such things are more common than most people will admit to.

So ONLY x10 M.... now is is ME or does x10 seem about right?

 

[MedicinalUser247]

I always have a hard time Designing Opiates for some reason. I think I'll stick to Phenethylamines and Tryptamines.

 

[4DQSAR]

I feel the KEY takeaway is that analgesia in a rodent model is NOT the same as the subjective effects in man.

As soon as a ligand becomes unselective, it's often hard to untangle what proportion of the activity is mediated by it's MOR activity.

Hence things such as cyclorphine being stated as 'as potent as carfentil' when in fact, we know that in every other case, an N-2-cyanoethyl moiety replacing an N-methyl moiety produces compounds that ARE much more potent analgesics but crucially, do not substitute for morphine. So the makers do not 'get' that there are at least five distinctive classes of opiate receptor but it seems that selectivity is a requirement.

I noted a couple of errors in the structural diagrams but in each case, probably a good thing - so accident or by design to make people think, derive and find the real structures? No idea.

Face it, we have a huge body of evidence suggesting that receptor occupancy time as well as selectivity play a part in the subjective effects i.e. things like nitazenes and fentanyl derivatives only produce 'plastic' euphoria at doses close to those that are fatal.

Heavens alone know why this 'potency is king' motif sprang from. As pure reseach, it all has value - but often the real value is knowing what doesn't work.

It also strikes me as an incredibly acquisitive marketplace. What's wrong with something say between morphine and oxymorphone in potency - assuming synthesis is trivial? I'm betting it's because whoever is making these dumb and dangerous RCs either cannot or will not scale. Which in itself MAY suggest that what we are seeing is some post-graduate 'working late' hence that scaling is impossible. I can't think of any other rational reason why ANYONE need go above x10M. A surprisingly large number of the MOST euphoric opioids have potencies of x10M or less. But if H is the 'gold standard' and has to be smuggled across the world, I sort of see the issue. But surely even 50% pure H could simply be replaced with a synthetic AND specifically syntehtics with a higher TI than H. It would still be a fraction of the bulk.

How trivial? You decide.

 

[MedicinalUser247]

Here's one I came up with... It's suppose to be a Half Opiate Half Dissociative Analog. https://ibb.co/k2B0n2VQ

 

[MedicinalUser247]

I was inspired by BQ-869. -> https://en.wikipedia.org/wiki/BQ-869

 

[4DQSAR]

Well READ THE PAPERS!

https://e-century.us/files/ijcep/8/2/ijcep0004620.pdf

No D-ring so that basic nitrogen is planer to the aromatics.

Bioactive molecules are theee dimentional and add occupancy time and what do you then get? The 4DQSAR

 

[Featherfall]

I feel the KEY takeaway is that analgesia in a rodent model is NOT the same as the subjective effects in man.

As soon as a ligand becomes unselective, it's often hard to untangle what proportion of the activity is mediated by it's MOR activity.

Hence things such as cyclorphine being stated as 'as potent as carfentil' when in fact, we know that in every other case, an N-2-cyanoethyl moiety replacing an N-methyl moiety produces compounds that ARE much more potent analgesics but crucially, do not substitute for morphine. So the makers do not 'get' that there are at least five distinctive classes of opiate receptor but it seems that selectivity is a requirement.

I noted a couple of errors in the structural diagrams but in each case, probably a good thing - so accident or by design to make people think, derive and find the real structures? No idea.

Face it, we have a huge body of evidence suggesting that receptor occupancy time as well as selectivity play a part in the subjective effects i.e. things like nitazenes and fentanyl derivatives only produce 'plastic' euphoria at doses close to those that are fatal.

Heavens alone know why this 'potency is king' motif sprang from. As pure reseach, it all has value - but often the real value is knowing what doesn't work.

It also strikes me as an incredibly acquisitive marketplace. What's wrong with something say between morphine and oxymorphone in potency - assuming synthesis is trivial? I'm betting it's because whoever is making these dumb and dangerous RCs either cannot or will not scale. Which in itself MAY suggest that what we are seeing is some post-graduate 'working late' hence that scaling is impossible. I can't think of any other rational reason why ANYONE need go above x10M. A surprisingly large number of the MOST euphoric opioids have potencies of x10M or less. But if H is the 'gold standard' and has to be smuggled across the world, I sort of see the issue. But surely even 50% pure H could simply be replaced with a synthetic AND specifically syntehtics with a higher TI than H. It would still be a fraction of the bulk.

How trivial? You decide.

i'd think its a bulk thing right? if a dose is 1000 times smaller than something like h or morphine, even if it feels worse and is gonna lose you some money, the benefits probably outweight it, at least, that has to be their logic. I once mathed out approximatly how many "doses" of carfentanyl vs how many doses of heroin were seized in Europe through the EUs drug report. It was a couple tons of heroin and only 6.81kg of carfentanyl and carfentanyls number were i think a full 0 bigger (billions compared to millions) while just approximated, its alot easier if the entire contients needed product for a year can fit in a handbag.

 

[4DQSAR]

i'd think its a bulk thing right? if a dose is 1000 times smaller than something like h or morphine, even if it feels worse and is gonna lose you some money, the benefits probably outweight it, at least, that has to be their logic. I once mathed out approximatly how many "doses" of carfentanyl vs how many doses of heroin were seized in Europe through the EUs drug report. It was a couple tons of heroin and only 6.81kg of carfentanyl and carfentanyls number were i think a full 0 bigger (billions compared to millions) while just approximated, its alot easier if the entire contients needed product for a year can fit in a handbag.

Well, given that even in the UK where the H is strong, as imported it's only about 76% pure (street is around 50%) and fetches circs £13500/Kg. So even if one only goes one order of magnitude and doesn't move bash, That still seems a LOT of money for a key of that theoretical material.

People NOT dying is probably the best way to stop a novel RC being banned but that said, right now in the US, it's almost certain that 'kratom extract' contains MGM-15 which would be extremly difficult to differentate from 7OHM but is some x240M in analgesic activity.

 

[Featherfall]

Well, given that even in the UK where the H is strong, as imported it's only about 76% pure (street is around 50%) and fetches circs £13500/Kg. So even if one only goes one order of magnitude and doesn't move bash, That still seems a LOT of money for a key of that theoretical material.

People NOT dying is probably the best way to stop a novel RC being banned but that said, right now in the US, it's almost certain that 'kratom extract' contains MGM-15 which would be extremly difficult to differentate from 7OHM but is some x240M in analgesic activity.

the x240M is actually mgm-16 which isnt availabe yet, mgm-15 is i think just slightly stronger than 7-oh

 

[4DQSAR]

the x240M is actually mgm-16 which isnt availabe yet, mgm-15 is i think just slightly stronger than 7-oh

My mistake - thank you for the correction. MGM-16 is the far more active. MGM-15 appears to be around 2-3x more potent then 7-OHM, itself so around x15M (in vitro rodent moded of anelgesia). So actually within the range I suggested? Of course, I am always the first to note that rodents can model pain, not subjective activity, and of course that mice are not men.

 

[Featherfall]

My mistake - thank you for the correction. MGM-16 is the far more active. MGM-15 appears to be around 2-3x more potent then 7-OHM, itself so around x15M (in vitro rodent moded of anelgesia). So actually within the range I suggested? Of course, I am always the first to note that rodents can model pain, not subjective activity, and of course that mice are not men.

yeah pretty much, i m just worried at mgm-16 hitting gas station markets eventually, that high of a potency is, even considering mice arent men, indicative of some potential issues

 

[4DQSAR]

yeah pretty much, i m just worried at mgm-16 hitting gas station markets eventually, that high of a potency is, even considering mice arent men, indicative of some potential issues

That -F is an absolute sod to add to the aromatic ortho of the methoxy moiety. Likely para substitution would be more favoured so mixed product.

Fluorinating agents are unforgiving in the main, the workarounds are known generally, but optimizing such a thing would be a long-term plan. I do not believe the 'cooks' who make 7OHM or even MGM-15 would think long-term.

I suspect the first we will hear IF someone attempts the synthesis at scale is their own deaths.

18F is used as a radio-ligand so a lot of work has gone in to finding more friendly routes, but these are milligram scale routes. If a reaction is exothermic, at microscale that wouldn't even be detected. But just look at the T2 Laboratories explosion and fire. Turns out the two geniuses tried it out at bench scale and ASSUMED it would be fine at scale!

It was not fine.

HF kills a lot more people per annum than people know. It isn't a strong acid so a spill will not burn immediately. It's more that the F- ion gets into the body and eats the bones. Spill on a limb - doctors cut of the limb to save the life (if possible). Here's a spectacular example of people who had used HF year in year out and made ONE mistake ONCE.



It's not that I mind cooks killing themselves, if they choose to undertake a dangerous process at scale, that's their choice. But killing others is not cool.

 

[Featherfall]

That -F is an absolute sod to add to the aromatic ortho of the methoxy moiety. Likely para substitution would be more favoured so mixed product.

Fluorinating agents are unforgiving in the main, the workarounds are known generally, but optimizing such a thing would be a long-term plan. I do not believe the 'cooks' who make 7OHM or even MGM-15 would think long-term.

I suspect the first we will hear IF someone attempts the synthesis at scale is their own deaths.

18F is used as a radio-ligand so a lot of work has gone in to finding more friendly routes, but these are milligram scale routes. If a reaction is exothermic, at microscale that wouldn't even be detected. But just look at the T2 Laboratories explosion and fire. Turns out the two geniuses tried it out at bench scale and ASSUMED it would be fine at scale!

It was not fine.

HF kills a lot more people per annum than people know. It isn't a strong acid so a spill will not burn immediately. It's more that the F- ion gets into the body and eats the bones. Spill on a limb - doctors cut of the limb to save the life (if possible). Here's a spectacular example of people who had used HF year in year out and made ONE mistake ONCE.



It's not that I mind cooks killing themselves, if they choose to undertake a dangerous process at scale, that's their choice. But killing others is not cool.

i see, i assumed flourination alot simpler but i was completely wrong there thats good to know. Thats good to know thank you for explaining

 

[Smyth2]

Risperfentanyl