DA transporter inhibitor & Mu Agonist?

[LikeADaVinci]

Of course I understand that the D2/3/4 dopamine targeting is not the same as the dopamine active transporter / synaptic vesicular transport — it’s not a PURE mu/DAT ligand, yet, but I’ve only been working on it for 24 hours … if I discovered the right compound I’d be patenting it rather than using it to try and win an argument on some Internet forum.

I have studied the quantitative structure activity for opioids, and have found that, in morphinons, the tertiary amine when substituted with a n-phenethyl moiety is not an antagonist but rather an agonist (unlike n-methylcyclopropyl or n-methyvinyl) with increased potency and tighter binding affinity

Anything else?

 

[AlsoTapered]

But your image ISN'T a morphinan (note spelling), is it?

So you don't even know the CLASSES of opioid, or even how to spell them - boy, embarrassing.

Alvimopan is the closest researched compound to your scribble. and WOW, it's an ANTAGONIST.


There ARE some rules that would IMMEDIATKY spot a phenylpiperidine compound opioid as being an antagonist so I suggest you LEARN them.

BTW you are drawing chiral compounds without providing chiral markings... so for a start, the image is actually TWO compounds and not one. If you can't even DRAW your targets... well, that isn't exactly reassuring.

As it turns out the compound IS known so you could have copied the SMILES string into PubChem and actually READ the research.

​

 

[vecktor]

Of course I understand that the D2/3/4 dopamine targeting is not the same as the dopamine active transporter / synaptic vesicular transport — it’s not a PURE mu/DAT ligand, yet, but I’ve only been working on it for 24 hours … if I discovered the right compound I’d be patenting it rather than using it to try and win an argument on some Internet forum.

I have studied the quantitative structure activity for opioids, and have found that, in morphinons, the tertiary amine when substituted with a n-phenethyl moiety is not an antagonist but rather an agonist (unlike n-methylcyclopropyl or n-methyvinyl) with increased potency and tighter binding affinity

Anything else?

Make it, Taste it or test it. In reality that is the only way to find out.
Then hang some more stuff off it to reduce the number of off target interactions whilst retaining the desired profile. I would guess as it stands there will be some interesting off target interactions with the drawn structure, This could easily keep someone busy for a while. the structure is pretty easy to make and play with. I wish you luck, if you get it right then you might discover something that is safer, better, shinier, cheaper whatever.

I doubt your drawn compound has not already been made and assayed, it is pretty obvious, a quick search turned up a couple of hits,
where simple 3 phenylpiperidine opioids are discussed, N-methyls are weak analgesics but it appears the N- phenethyl derivatives are active and not as antagonists in the example series. this paper also suggests that 3-hydroxy on the phenyl ring is needed for any activity whether agonist or antagonist.
https://doi.org/10.1002/jcc.540070414 on sci hub.

the N- phenethyl derivatives have significant activity in the range of meperidine (ref 11). N-phenethyl substituents also consistently increase activity optimally in rigid phenyl-axial compounds in the morphine, morphinan, and 6,7-benzomorphan classes of opioids

Ref (11) M.A. Iorio and A. F. Casy, J. Pharm. Pharmacol.,27, 140 (1975).

I haven't go the time to get the Ionio and Casy paper and read it but it probably contains answers, that or ref 16 which unfortunately is not copied on the sci hub version of the the paper.

Swiss target prediction is not really very reliable. Actually it is really bad. It is ok as a starting point but that is about it.

You are correct about the N-phenylethyl in mu agonists sometimes N-cinnamyl works too, though that is quite general there are plenty of exceptions. Mu is pretty tolerant of structure, the large size of the natural ligand leaves lots of space for smaller molecules to take a pose in the binding pocket and still activate the receptor.

I'm sure tapered-fertile-haribo-piglet will share his opinion, though there is an old saying regarding opinions being like assholes.....

 

[AlsoTapered]

The compound drawn is in PubChem... someone did the work. No guesswork required.

OK they DO specify the (+) enantiomer but the raecemate was found first and as far as I can tell the (-) does nothing.

You need a meta phenol to produce antagonist activity. Even the N-allyl and N-methylcyclopropyl homologues of pethidine and prodine are weak agonists...

But then look at ketobemidone. It's an island of agonism ALTHOUGH picenadol MIGHT suggest the reason why ring-substituted ketobemidine derivatives were seemingly antagonists. One of the four MAY be a (quite potent) agonist but the other three are all antagonists.

It's often the case that we simply don't have all the data. Those books missed out quite a few classes of opioid. But fair play, no Reaxys or PubChem back then - someone went through every paper with the word 'analgesic' in it, by the looks of it.

 

[LikeADaVinci]

But your image ISN'T a morphinan (note spelling), is it?

So you don't even know the CLASSES of opioid, or even how to spell them - boy, embarrassing.

Alvimopan is the closest researched compound to your scribble. and WOW, it's an ANTAGONIST.


There ARE some rules that would IMMEDIATKY spot a phenylpiperidine compound opioid as being an antagonist so I suggest you LEARN them.

BTW you are drawing chiral compounds without providing chiral markings... so for a start, the image is actually TWO compounds and not one. If you can't even DRAW your targets... well, that isn't exactly reassuring.

As it turns out the compound IS known so you could have copied the SMILES string into PubChem and actually READ the research.

​

Wow … I’m sooo embarrassed. …. A man on an Internet forum knew more than I did about a topic i just started researching … let me go cry under a rock for the rest of my life?

 

[AlsoTapered]

No - everyone on BL get's to see your ignorance and laziness. If I can find the papers regarding your mystery chemical in 60 seconds, so can you. PubChem is free and accessible to all.

Every 10-12 weeks we get someone who finds that software and thinks themselves an instant expert. Don't forget, some BLers are actually educated in this subject. None of them use it... because experience shows it's junk.

'Dresden's Chemical Fluff Thread (Name-A-Molecule' is the appropriate place to post such items.

​

 

[negrogesic]

Wow … I’m sooo embarrassed. …. A man on an Internet forum knew more than I did about a topic i just started researching … let me go cry under a rock for the rest of my life?

You seem to be skipping a few rungs of understanding that are the prerequisites to making meaningful progress if one were intent on achieving such a thing, if possible. So if you truly are determined to learn, it would behoove you to not be unnecessarily argumentative when discussing these ideas. The more wrong one is the more opportunities they have to learn, it's a valuable thing when someone can provide guidance/insight

 

[AlsoTapered]

It's a pity that synthesis discussion is precluded because it's actually one of those rungs that is a vital brik in medicinal chemistry. The act of finding a route essentially teaches people retrosynthetic strategy.

If people had to post the route TO a compound, they would soon realize that while software will allow the user to draw ANY structure as long as the valency balances, a rough estimate (up to 24 atoms) was that only about 0.1% of what's POSSIBLE to draw is actually possible.

ChemSketch, PubChem Google Patents are all free. Library Genesis (among others) will provide most articles and of course their are quite literally thousands of hotlinks to papers in the 'Useful neuroscience/pharmacology threads', including the pharmacophore (as much as is written) of opiate ligands.

I was actually surprised that (to the best of my knowledge) nobody has ever written down the fact that antagonists require a meta phenol.

 

[Neuroprotection]

“Forgive me, but wouldn't it be much easier to produce a codrug that is metabolized into an opioid and a DRI? Much simpler.”

Sure, it would be much simpler, but the best things in life usually aren’t the easiest … I’m trying to for the first time specifically model a single molecule which is both dopaminergic and analgesic — if not to alleviate the deadly respiratory depression, then to increase the quality of life of patients nodding out taking high doses of oxy / fentanyl for cancer pain, for instance …

Why the resistance to finding a single compound that does both?

I don’t think anyone is really resisting it, but rather, there’s just not enough perceived or actual incentive to develop such a compound. you made reference to an opioid with DRI Activity, potentially improving the lives of cancer patients, well, as I already mentioned in my previous reply, the cheaply available and well studied psychostimulant methylphenidate has been given in combination with opioids for exactly that purpose.
I do understand your frustration, it would be wonderful to have such a compound with a nice combination of MU agonist, and DRI actions. I would be more than happy to try such a compound, though I probably shouldn’t given my addictive personality.
I wish you the best of luck and I do hope you do get success in your search. to be honest, I think you would be better developing a compound with very powerful and long acting highly selective Kappa opioid antagonist affects with a simple structure and less toxicity to the previous compounds. Kappa antagonists may well reverse the reward deficiency/anhedonia associated with drug withdrawal. unfortunately, the long acting powerful antagonist used in animal studies have difficulty crossing through the blood brain barrier and one of them resulted in cardiac rhythm disturbances in a trial patient leading to them being discontinued and trials terminated before results could be seen in humans. Currently available kappa antagonists under investigation for human use are very short acting and much weaker, which may not be sufficient to produce the highly beneficial effects seen in animal research. developing a highly selective, long acting, and incredibly strong Kappa antagonist that easily crosses the blood brain barrier and is safe in humans would be a much more worthwhile endeavor.

 

[AlsoTapered]

@Neuroprotection Nortilidine more or less fulfils the brief. It's interesting that the effects of fencamfamine are partly reversed by naloxone so one would think it a reasonable start-point. US Patent 4291059 "Cycloaromatic compounds, analgesic Properties thereof and Method of use thereof as analgesic" overlays camfentamine (the N-methyl homologue of fencamfamine) perfectly but the latter lacks the benzylic ester function.

The problem would be adding that ester (or moiety that could be converted to ester). Fencamfamine/camfentamine use a Diels-Alder reaction. MAYBE the use of (3E)-4-nitro-2-phenylbut-3-enenitrile or [(2E)-1-methoxy-3-nitroprop-2-en-1-yl]benzene offer routes to a benzylic ester but those aren't exactly common chemicals and reduction of the alkene and the reeduction and monoalkylation would be difficult.

Like tilidine itself, it's a small molecule but it packs in a lot of moieties and 4 enantiomers so unless luck is with you, quantitative yields would actually only result in a 25% yield.

Every year I go back to that reversed-ester of nortilidine to see if a commercial precursor has become available and while some cool new reagents have appeared such as N-(2,4-dinitrophenoxy)methanamine (Oxirane to N-methyl aziridine directly), it's still not facile.`

 

[Neuroprotection]

@Neuroprotection Nortilidine more or less fulfils the brief. It's interesting that the effects of fencamfamine are partly reversed by naloxone so one would think it a reasonable start-point. US Patent 4291059 "Cycloaromatic compounds, analgesic Properties thereof and Method of use thereof as analgesic" overlays camfentamine (the N-methyl homologue of fencamfamine) perfectly but the latter lacks the benzylic ester function.

The problem would be adding that ester (or moiety that could be converted to ester). Fencamfamine/camfentamine use a Diels-Alder reaction. MAYBE the use of (3E)-4-nitro-2-phenylbut-3-enenitrile or [(2E)-1-methoxy-3-nitroprop-2-en-1-yl]benzene offer routes to a benzylic ester but those aren't exactly common chemicals and reduction of the alkene and the reeduction and monoalkylation would be difficult.

Like tilidine itself, it's a small molecule but it packs in a lot of moieties and 4 enantiomers so unless luck is with you, quantitative yields would actually only result in a 25% yield.

Every year I go back to that reversed-ester of nortilidine to see if a commercial precursor has become available and while some cool new reagents have appeared such as N-(2,4-dinitrophenoxy)methanamine (Oxirane to N-methyl aziridine directly), it's still not facile.`

Really sorry, but my knowledge of chemistry is extremely poor, so most of that went straight over my head. However, I certainly admire your level of knowledge of chemistry, I hope you can put it to good use and make us some new very exciting substances.
As for my personal opinion on the topic of OP, I would just take an already tried and tested stimulant with a well known opioid and I’m sure it’ll produce the same effects in terms of euphoria/recreational potential that OP was hoping for with their designer molecule.
I hope I’m not being demeaning, and I think it’s great to have a discussion about such ideas. however, would you agree with my assessment that as of now, developing a MU agonist opioid with DRI activity won’t really bring anything sufficiently special and novel to be worth the high research and production costs.

 

[Juicewrldfan]

Demerol - dopaminergic opioid (DAT/NET + Mu Opioid agonist)
Tramadol - Mu Opioid + SERT/NET

Methylphenidate (Ritalin) + Oxycodone (Oxy-IR) were the only drugs in my entire life to give me true overpowering euphoric pleasure. Wish I could’ve taken them together 20 years ago when naive to every substance

Brompton Cocktail or an I.V. Speedball …..just pure heavens

Is Demerol any good? I had it one night but I’m wondering if it was fake because I was snorting them back when. I used to do shit like that and they didn’t do much tbh…I take it you’ve had it. What was your experience?

 

[AlsoTapered]

Pethidine (demerol) isn't much. Among 'true' opiate users it's referred to as 'dummy oil' because it's actually even less effective at reversing withdrawal syndrome than codeine.

It's only used because it's so cheap and so well established. If it were discovered today it would never get an ML.

TI of morphine is 70.
TI of pethidine is 4.7.

Need I say more.

BTW even morphine isn't THAT great. Fentanyl has a TI of 400 and sufentanil has a TI of 26,700. So people ODing on fentanyl... just WOW. The size of their habits must be off the scale.

 

[someguyontheinternet]

Nucleus accumbens dopamine release doesn't impinge on breathing. If there is too much inhibitory at the medulla respiratory depression will occur, hence why opioids cause respiratory depression despite disinhibiting dopamine release in the NA.

Came here to say this. If you're interested in respiratory depression the VTA->NAcc pathway is the wrong place to look

 

[LikeADaVinci]

Interestingly enough, 14-methoxy analogues of morphine seem to have little->no respiratory depression, while also being 500x more potent weight/weight. I don’t know why they haven’t been developed, being that they would be far more profitable (doses being 20mcg as opposed to 10mg) and there is much less potential for death.

I was actually planning to synthesize 14-methoxy codone from oxycodone using the Williamson ether synthesis (NaH/ICH3 & THF) to test it out on myself … I can’t find much literature at all on the 14-methoxy analogue of oxycodone but I’m finding lots of data on compounds like 14-methoxymetapon which has a Ki of 0.15nm

 

[someguyontheinternet]

Gprotein biased agonists exhibit lower respiratory depression because they aren't activating receptors bound to beta arrestin, that may be what's happening if what you say is true

 

[Skorpio]

Interestingly enough, 14-methoxy analogues of morphine seem to have little->no respiratory depression, while also being 500x more potent weight/weight. I don’t know why they haven’t been developed, being that they would be far more profitable (doses being 20mcg as opposed to 10mg) and there is much less potential for death.

I was actually planning to synthesize 14-methoxy codone from oxycodone using the Williamson ether synthesis (NaH/ICH3 & THF) to test it out on myself … I can’t find much literature at all on the 14-methoxy analogue of oxycodone but I’m finding lots of data on compounds like 14-methoxymetapon which has a Ki of 0.15nm

Williamson is pretty messy, starting from an acyl chloride is likely to be more selective.

 

[AlsoTapered]

Interestingly enough, 14-methoxy analogues of morphine seem to have little->no respiratory depression, while also being 500x more potent weight/weight. I don’t know why they haven’t been developed, being that they would be far more profitable (doses being 20mcg as opposed to 10mg) and there is much less potential for death.

I was actually planning to synthesize 14-methoxy codone from oxycodone using the Williamson ether synthesis (NaH/ICH3 & THF) to test it out on myself … I can’t find much literature at all on the 14-methoxy analogue of oxycodone but I’m finding lots of data on compounds like 14-methoxymetapon which has a Ki of 0.15nm

Yeah, that's the research by Helmut Schmidhammer I mentioned.

It wasn't developed because it didn't offer a significant clinical advantage. The doses of opioids used to treat pain only produce respiratory depression in a small minority of patients and such at risk groups have the dose carefully titrated.

I don't think it even reached human trials.

Schmidhammer has spent 25 years and published 139 articles (and a dozen patents) on QSAR analysis. I don't think the goal is to produce a medicine but to explore the QSAR of the morphinans. He has that which well all seek - tenure!

Helmut Schmidhammer

Loop is the open research network that increases the discoverability and impact of researchers and their work. Loop enables you to stay up-to-date with the latest discoveries and news, connect with researchers and form new collaborations.

loop.frontiersin.org

How do you plan to convert oxycodone to 14-hydroxycodone? The original route from codeine to oxycodone has 14-hydroxycodone as an intermediate; that seems a better option because at least its well documented. It's for a commercial product so it will be somewhat optimized.

@Skorpio can you use an acyl chloride for a methyl ether? Phosgene? I seem to remember finding a methodology for reducing formate esters to methyl ethers but it did not seem too friendly.

 

[Skorpio]

Yeah, that's the research by Helmut Schmidhammer I mentioned.

It wasn't developed because it didn't offer a significant clinical advantage. The doses of opioids used to treat pain only produce respiratory depression in a small minority of patients and such at risk groups have the dose carefully titrated.

I don't think it even reached human trials.

Schmidhammer has spent 25 years and published 139 articles (and a dozen patents) on QSAR analysis. I don't think the goal is to produce a medicine but to explore the QSAR of the morphinans. He has that which well all seek - tenure!

Helmut Schmidhammer

Loop is the open research network that increases the discoverability and impact of researchers and their work. Loop enables you to stay up-to-date with the latest discoveries and news, connect with researchers and form new collaborations.

loop.frontiersin.org

How do you plan to convert oxycodone to 14-hydroxycodone? The original route from codeine to oxycodone has 14-hydroxycodone as an intermediate; that seems a better option because at least its well documented. It's for a commercial product so it will be somewhat optimized.

@Skorpio can you use an acyl chloride for a methyl ether? Phosgene? I seem to remember finding a methodology for reducing formate esters to methyl ethers but it did not seem too friendly.

I misspoke when i said acyl chloride. I meant chlorinate the oxycodone and then react that with a methyl donor alcohol.

I am working with basic undergrad organic knowledge, so i don't really have the nuance. Would you need to install protecting groups with williamson?

 

[AlsoTapered]

@Skorpio Either way it's still a Williamson Ether synthesis, isn't it?

NaH has obvious disadvantages but I think it was chosen because steric hinderance is an issue.

Ag2O might be an alternative but it's still just a variation. Might be worth considering as long as the phenol is protected.

Life is so unfair. If only one could synthesize the ester and reduce it, but you can't do that with formate esters.

When you look at the entire synthesis which Schmidhammer improved upon (based on the patents), it's clearly not designed to be scaled. It's certainly valuable in understanding the QSAR of the class but experience has taught me that so many steps results in huge costs on the commercial scale.

In the 60s Janssen openly stated that he gave up on researching the 3,3-diphenyl heptanone class and concentrated on the anilidopiperidines because HTS was so much cheaper. A bit of a shame because dextromoramide really is an island of activity. But it's chiral and as he found the pharmacore of the 3,3-diphenyl heptaones, he realized that their would be too many enantiomers.