Tapentadol ≈ Picenadol

[Feretile]

When it comes to modern opioid design, numerous training-sets and 3DQSAR studies have identified 6 moieties that when in an appropriate distance from the A aromatic (almost always a benzene or phenol) will provide affinity. Further research identified modification to those moieties that will provide agonist, partial agonist and silent agonist (also termed antagonist) compounds.

In an attempt to show people a very simple example, I enclose images of 2 opioids that may look totally unrelated at first glance but to the opiate receptors, act in an almost identical manner save that one is an agonist, the other a partial agonist... although modification to produce a fill agonist would be a trivial task.

tp hosted at ImgBB

Image tp hosted in ImgBB

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[Feretile]

It's important to remember that when we draw a chemical, we are sketching a 3D compound onto a 2D surface which is why we use wedges (towards viewer) and dotted wedged (away from viewer).

As you can see, tapentadol & the agonist isomer of picenadol overlay almost perfectly. The only difference is that tapentadol has an ethyl side-chain on the benzylic carbon whereas picenadol has an N-propyl. The researchers were careful not to include the N-propyl homologue in the patent, possibly so that RC manufacturers did not observe it and produce an agonist homologue thus:

 

[Feretile]

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Image tahexadol hosted in ImgBB

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So, above is the full agonist. WHY is the n-propyl moiety important? Well I have not read any compelling reason why it should be so but if you consider esters (e.g. pethidine/demerol) which has 3 methylenes (-CH2-) with an O spacer. Reversed ester (e.g. prodine) which has 3 methylenes (-CH2-) with an O spacer, ketones (e.g. ketobemidone) which has 3 methylenes (-CH2-) with a =O side-chain.

Another example of a partial agonists is mazindol.

An example of an antagonist is alvimopan.

But the MAIN point that I am making is that while tapentadol is a class A drug in the UK (and I presume strongly controlled in the US), my analogue may be chemically similar but it's activity is VERY different. Oh, and if you want something that looks different but does the same, you need a bioisostere:

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Image tapentamide hosted in ImgBB

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It does not seem to be widely known, but an aryl carboxamide will produce a compound with identical affinity to a compound with an aryl hydroxyl (phenol). Now, generally it's more difficult to synthesize the amide but it's VERY useful if a designer wishes to alter the LogP of a candidate drug.

 

[Feretile]

LogP of tapentadol is 3.23, the LogP of the carboxamide bioisostere is 2.83. The LogP of taxexadol (the full agonist) is 4.09 so it should be considerably more potent. Not AMAZING, but maybe M potency.....

So, since tapentadol is now widely used in medicine, I would expect multiple patents on more efficient synthetic pathways..... watch this space.

Oh, last point - if you wonder how they resolve the 4 diastereomers to isolate just the 1 compound they want. Nothing more complex than (S) naproxen is used. I find that elegant. They use a very, very, very cheap chiral medicine in order to resolve a more expensive medicine....

 

[izo]

the logp of tapentadol is higher than that of the carboxamide? i though amides are somewhat neutral in comparison to the slightly acidic alcohols. i thought that the logp is more correlated to the pks.

 

[Feretile]

Well, I did use the Molinspiration LogP calculator. I mean, I know how inaccurate these estimates are but it's a Log scale so those two values are quite different.

I first spotted that a carboxamide substituted for a phenol in papers concerning 8-CAC. 8-CAC is an opioid antagonist designed as a putative treatment for cocaine dependence. One of the major problems with cyclazocine is it's short duration and so the researcher Mark. P. Wentlansd came up with a general 2-step synthesis to convert a phenol to a carboxamide.

I think it's a very useful synthetic step. He also used it to modify morphine and it's duration was over 24 hours. Considering how cheap morphine is ($809/Kg), I cannot help thinking that If it means that people stay with the program, it's worthwhile. I guess drugs like ketobemidone could also be similarly modified.

I THINK the lower LogP explain the slightly lower potency. Oh, and another unexpected find - the carboxamide is chiral! Only one of the 2 isomers is active).

I do not have a lot of time for these ultra-potent opioids. I would much rather find something that is as potent as M as an opioid, as potent as amphetamine as a DRI and as potent ad K as an NMDA antagonist. Such a compound exists and I have spent 9 years (so far) finding a simple (3 steps or less) synthesis. I HAVE found one, but it uses:

www hosted at ImgBB

Image www hosted in ImgBB

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I have found a 2020 paper which suggests that this is an alternative:

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Image ssss hosted in ImgBB

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Ultimately, it's 1 step to convert an alkene to an N-methyl azetidine.

I have also looked at the Sharpless hydroxyamination but even with Sharplesses genius, yield is just not amazing. As it is, an N-methyl azetidine can be converted to an alpha propionoxy methylamine moiety. A VERY small molecule but a very difficult one to manipulate.

 

[izo]

I first spotted that a carboxamide substituted for a phenol in papers concerning 8-CAC.

i first saw it on some morphinan or phenanthren type opioid, i dont find it again atm but it might already have had an INN.

 

[Feretile]

It'd one of those problems where one has to keep up to date with the latest papers.

I still say Levophacetoperane (Lidépran, Phacétoperane) represent the next big thing. I am quite open to talking bout it because I have my own store (gathered over 15 years) of much, much better ligands. You want a modern methaqualone? I got it. 10mg equates to 300mg methaqualone. You want an alcohol mimic, wait for the patent, you want a high-potency opioid that can be made in 1 step, I got it.....

I do not have a full set by any means but with the methaqualone analogue, I tried it, my wife tried it & my son tried it (along with several people I worked with) and we all felt that it 'too good'.

As for U-47700, we already have an analogue that has an almost identical synthesis (one precursor changed) than increases potency by a factor of 4 (8 unless people resolve isomers).

As for a free, high potency opioid:

ici hosted at ImgBB

Image ici hosted in ImgBB

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I found this in a German paper. The parewnt compound was x60M orally, this was x250 and that was without resolution. It's not a stronger mu agonist but in addition to it's mu activity, it's also a potent NOP agonist. You will note that the carboxamide is the bioisostere of a secondary hydroxyl but I believe that it's the bond angle that is key.

I overlaid it with a potent NOP agonist and the -NH2 orerlaid the N of an amine found in a selective NOP. I guess that it isn't x4 in it's ability to sustain someone with an opioid habit but it is far, far more euphoric. It's chemistry is far too complex to be made at scale and wholesaled which is why it was never used.

I am looking at nortilidine homologues. If you didn't know, the effects of fencamfamine (and camfentasmine) are partially reversed by naloxone and if you overlay camfentamine with nortilidine, you wull note that aromatic & N: overlay perfectly. THAT is my field of interest. Not some stupid x5000 opioid but something M potency that is also a DRI as potent as amphetamine and NMDA activity as potent as ketamine. This is not something that would change hands at £5/10 for a tiny bag but at £100 per gram.

Assuming it's T1/2 is huge.

Experience and some semblance of morality means that I want people to enjoy a well designed and well tested ligand. I am sick of people who just GUESS at the next in a class. I mean, people who are making K analogues with a cycloheptane ring! Especially since I posted a link with the QSAR of thianes.....

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Image who hosted in ImgBB

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Does one have to be a genius to realise that this is an obvious step?

European Journal of Medicinal Chemistry | Vol 33, Issue 1, Pages 3-77 (January 1998) | ScienceDirect.com by Elsevier

Read the latest articles of European Journal of Medicinal Chemistry at ScienceDirect.com, Elsevier’s leading platform of peer-reviewed scholarly literature

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[izo]

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i had the cyclohexyl version of this i believe (didnt sent it in). it wasnt really potent and felt almost gabaergic, and like a very weak dissociative.