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Tramadol Turns Out to Be a Natural Product

Every so often reports appear that some synthetic compound actually turns out to be a natural product. Sometimes these make very little sense, and turn out to be analytical mistakes (as with this report of nevirapine). But sometimes they’re right.
This one looks as if it’s right, though. Nauclea latifola, known colloquially as the “African peach”, apparently has tramadol in it. That’s pretty interesting, since tramadol was previously known as a synthetic opioid agonist (among other activities), used as an analgesic since the 1970s. Fittingly, preparations from this same species show up in a number of traditional medicine mixtures in West Africa, and there have also been numerous reports that extracts of the tree’s roots have an analgesic effect.
This work was done through classic natural-products work: fractionate the root, test the fractions for activity in a rodent assay, home in on the active fraction and see what compounds are in it. It’s always good to read about this sort of thing working – a lot of natural products were discovered this way in earlier days, but it’s gotten harder over the years. Too often, there will be some extract that shows activity, which would be worth following up on if it concentrated, but none of the fractions are then particularly interesting. Here’s a writeup at Chemistry World:

Our results indicate that high amounts of the analgesic drug, tramadol, can be obtained through a simple extraction procedure from Nauclea latifolia found in Cameroon or sub-Saharan areas,’ says Michel De Waard, a neuroscientist at the Université Joseph Fourier. De Waard adds that the root of the plant could be viably used as a source of tramadol because of the significantly high concentrations of the drug – over 1% of the original dry content.
The team used NMR and HRM spectroscopy, as well as x-ray crystallography, to determine the structure and confirm it as tramadol. Further spectroscopic and isotope ratio analyses confirmed that the compound extracted was indeed natural in origin, and not a by-product of cross-contamination. This unexpected discovery supports the traditional uses of N. latifolia roots in the treatment of pain; however, although other parts of the plant are also used in traditional remedies, the team found no analgesic compounds in the rest of the plant.

It’s interesting that tramadol is made in such high concentrations, and it’s worth speculating about what benefit the tree gets by spending that much metabolic effort. The same group that reported this isolation is now looking at the biosynthesis, and that should be worth hearing about.
Some readers, especially those outside the field, might wonder why I give this work a stamp of approval while instantly rolling my eyes at the nevirapine isolation paper. There are several reasons. One is that there are most certainly natural products that target the opioid receptors, starting with morphine and moving along from there. Natural products that potently inhibit reverse transcriptase (the target of nevirapine) are unknown to me. Nevirapine is also an unusual structure to propose as a natural product. By this point, we’ve isolated enough plant-derived compounds that most of the time a natural products chemist can say “Oh yeah, that’s a terpenoid, looks related to such-and-such”, or “Oh yeah, that’s an alkaloid of the this-and-that family”. Nevirapine does not fit easily into such classifications, and complete outliers like this are becoming more and more rare. If you find one, you make a big deal out of it. The last straw about the nevirapine paper was that it blithely mentioned that the compound was optically active, which was (see that earlier link for more) unlikely enough that it also would have been worth a separate paper. The fact that it was just mentioned in passing called the whole manuscript into question. The present paper suffers from none of these defects. Tramadol has certainly never been reported as a natural product, and it’s interesting that it is one, but looking at its structure, you could imagine that sure, a plant could make that, one way or another.

27 comments on “Tramadol Turns Out to Be a Natural Product”

  1. wim says:

    Pretty odd that the natural tramadol is racemic, though, no?

  2. ScientistSailor says:

    Aristeromycin, a carbocyclic nucleoside, was synthesized before it was discovered as a natural product:
    http://pubs.acs.org/doi/abs/10.1021/ja00308a047
    What are the other ones?

  3. weirdo says:

    Wim: Yes, that caught my eye too; however, the authors call it out specifically and the finding prompted them to re-evaluate everything they did and replicate it (triplicate it, so to speak). Nicely done, I’d say.

  4. RKN says:

    One of my dogs was prescribed Tramadol. Maybe African Peach root extracts are available by mail, save me a few bucks?

  5. robopox says:

    “All natural pain relief from African peach extract” in
    woo-woo ‘supplements’ and ‘therapies’ in ….3…2…1…

  6. JoJo says:

    Histamine was synthesized before it was found to be a naturally occurring material.

  7. Michael H. Parker says:

    The good news is that now that tramadol has been found to be natural, it I will be safer to use with none of the side effects that plague synthetic drugs. 🙂

  8. paperclip says:

    @1, I’ve seen racemic natural products before. If that means 50% of the product is inactive, well, one thing I’ve learned from working with natural products is that sometimes the producing organism hardly acts like a careful craftsperson but more like a chef with ADD, making all kinds of different things including the one that is actually useful.

  9. samadamsthedog says:

    “Too often, there will be some extract that shows activity, which would be worth following up on if it concentrated, but none of the fractions are then particularly interesting.”
    iOADâ„¢ (i’m Only A Dog), but i’m intrigued. Are you saying that the extract is active but the fractions are not, or rather that the fractions are uninteresting for other reasons?
    If the former, the implied synergistic effect would appear to be far more “interesting” than if the fractions had been active.

  10. Anonymous says:

    @9
    The synergistic effects are indeed fascinating, …it’s piecing together which compounds, and at what concentrations (uM?, pM?, fM?), are doing it out of the hundreds present which is the nightmare

  11. Chris D says:

    We had a very interesting talk here at Marquette yesterday from Dan Armstrong (UT-Arlington). He told the story of the stimulant 1,3-dimethylamylamine (DMAA) that was claimed to be a natural product identified in geranium oil. This “claim” conveniently allowed the stimulant to be legally sold as a dietary supplement (hundreds in millions in sales)– no studies needed. What is stopping anyone from watering their plants with whatever drug they might want to sell? I’m surprised this loophole hasn’t been pursued more often.

  12. Bob Weiss says:

    Very cool stuff. Mother nature is one heck of a chemist.
    On a similar note, was there ever any independent confirmation of the reported presence of methamphetamine in certain acacia species?
    http://www.erowid.org/references/refs_view.php?ID=7161

  13. MoMo says:

    Triclosan is also a natural product, found in sea corals, although it’s hard to believe as the researchers only isolated 0.5 mg.

  14. Algirdas says:

    @ScientistSailor,
    when was aristeromycin synthesized in the lab? I’m asking because the paper you link to, JACS 1985, refers to isolation of aristeromycin in 1968 by fermentation (ref1), but does not mention synthetic prep at all. The 1968 paper (http://dx.doi.org/10.7164/antibiotics.21.255) does not mention synthetic compound either.

  15. Trottelreiner says:

    @Bob Weiss:
    No, and last time I heard somebody talk about it, his guess was on contamination in the lab.
    That being said, I’m still somewhat sceptical on that one, though then, tramadol is quite close to morphine in structure, and if we assume this uses phenethylamine instead of dopamine, we get quite close:
    http://www.scs.illinois.edu/denmark/presentations/2006/gm-2006-1=31R.pdf

  16. ScientistSailor says:

    @14. Algirdas. I may have been wrong about that. I always believed it was so, but I can’t find a synthesis paper that predates this 1967 structure paper:
    http://pubs.rsc.org/en/content/articlelanding/1967/c1/c19670000852#!divAbstract

  17. leftscienceawhileago says:

    Derek,
    We need a post on older medicines that have been validated in modern times. Humans got plenty of things wrong (e.g.KAu(CN)2 for tuberculosis), but it blows my mind that we even able to get one thing right!
    I can think of artemisinin, cyclotides, asprin…
    Were we just lucky? Was it low hanging fruit? Did we pay a massive cost in deaths due to experimental therapies?
    Or were some of these effects easily resolved without the use of (modern) double blind clinical trials? Was it our social structure that allowed effective therapies to propagate?

  18. DrFreddy says:

    This means tramadol is no longer an opioid, but an opiate now, right? All text books to be amended! Amazing.

  19. Morten G says:

    If you have a synergistic effect… Actually I would only believe it was a synergistic effect if all fractions were negative but mixing them back together rescued the effect. Pretty sure that isn’t done enough. Too many things can go wrong during purification/fractionation, especially when you don’t even know what you are looking for.

  20. Morten G says:

    And if you can rescue the effect by defractioning into one big pot then you should be able to deconvolute the active fractions by defractioning into to pots. If one is active then defraction then fractions that went into that pot again. If neither is then defractionate across so each of the two pots you get then are 50% from the each of the previous pots. Iterate. It should be pretty straight forward. Might be dull.

  21. Paul D. says:

    If someone patents a compound, then that compound is discovered in nature, does that invalidate the patent (on the compound itself, not a patent for a synthesis of the compound)?
    A patent on Tramadol would have long since expired, of course.

  22. Vladimir Chupakhin says:

    Does anyone know other similar examples?

  23. George says:

    This is probably coincidence but at about the time that the plant was discovered, the FDA and the DEA took action to make Tramadol a scheduled (IV) drug as of August 18th 2014.
    While the discovery of the a synthetic molecule is incredible, it has happened before, as other posts indicate. What makes this discovery unique is that the concentrations of the drug found in the root bark are actually at therapeutic levels! A simple extraction of a small amount of bark yields about 400 mg of product

  24. Harry says:

    This has now been proven to be a case of anthropogenic contamination. The paper has been published in Angewandte Chemie Int. Ed. as a VIP paper and highlighted by Nature.
    So it’s not a natural product afterall.

  25. Harry says:

    This has now been proven to be a case of anthropogenic contamination. The paper has been published in Angewandte Chemie Int. Ed. as a VIP paper and highlighted by Nature.
    So it’s not a natural product afterall.

  26. Harry says:

    This has now been proven to be a case of anthropogenic contamination. The paper has been published in Angewandte Chemie Int. Ed. as a VIP paper and highlighted by Nature.
    So it’s not a natural product afterall.

  27. Harry says:

    This has now been proven to be a case of anthropogenic contamination. The paper has been published in Angewandte Chemie Int. Ed. as a VIP paper and highlighted by Nature.
    So it’s not a natural product afterall.

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