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Kratom alkaloids as structural opiods

fastandbulbous

fastandbulbous

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The plant kratom (M. speciosa) has been used in its native Thailand to treat opium addiction, and alkaloids found in the plant have been discovered to have mu opiate receptor agonist activity.

Some people find it difficult to believe that an indole/tryptamine alkaloid, with a close relationship to psychedelic tryptamines and yohimbine could possess opiate activity, but the alkaloids found conform to the basic chemical structure requirement needed for mu agonist activity

59655basic_requirement_for_opiate.JPG


The main alkaloid, mitragynine has some mu and delta opiate agonism, but the most active agonists are the alkaloids which have the pseudoxindole structure. Shown below are the structures of mitragynine and the correspondind pseudoxindole, with the basic opiate requirement skeleton shown in red

59655Mitragynine_as_structural_opiod.JPG


As can be seen, both consist of a phenyl ring separated from a tertiary amine by 3 carbon atoms. Mitragynine does not fully match the structure, as the carbon atom (noted by *) attached to the phenyl group needs to be fully substituted for maximun agonist activity, and most probably accounts for why the pseudoxindole is the most active compound structure (and is closest to the required bond angles due to sp3 hybridization).

Quite why these alkaloids have opiate activity, but other similar ones, such as yohimbine, do not is a bit of a mystery to me at the minute, but any further contributions/insights would be greatly appreciated
 
Firstly I took the upper structure and detached a bond to make for an easier to digest compound that clearly identifies with the piperidine backbone. I have a syntheses for making N-phenethyl-3-methyl-4-piperidone in my files. One could substitute the PEA for tryptamine and see how this fairs. Then I simply substituted the heterocylic ring with a well-known recipie for making the prodine class of drugs. Such a compound is already coveted in the analog acts, but it would help diagnose the opiate agonist activity of these kratom alkaloids.

That is the best that I can currently muster. However, i'll keep ye posted if I see anything else.
 

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Using the above post as a foundation, it can also be construed that the tryptamine heteronucleus can be incorporated on to Meperidine and Ketobemidone scaffolds. Given that the phenyl-n-propyl backbone cooperates favorably in such circumstances it is not such a massive deduction to spot that the tryptamine moeity could switch for this.

On a side note, notice the steps in the 'ketobemidone' recipie. One has there piperidone and does a Grignard reaction using m-bromoanisole. They then react the tertiary alcohol with thinyl chloride, react this with KCN, react this with EtBr (aka methadone). This reaction could also be done on the free hydroxyl in tramadol to give a ketobemidone-tramadol cross-hybrid. A meperidine-tramadol hybrid is also possible. A bit unlikely but just letting you know of the possibilites.
 

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hi,
you just forgot one important thing. the structures above don't show mitragynin, as mitragynin has a hydroxy attached on position 9 (on top of the phenyl)
and thats , at least in this substance, essential for opioid-activity.

the meta-hydroxy is found in many other opioids ( all morphine-relatives, ketobemidon, tramadol, masked as a nitro-group in etonitazen etc) and should be added to your basic structure requirement. :)
 
I was waiting for this, heh...maybe this'll be what tryptamines are to LSD.
 
morphiquet said:
hi,
you just forgot one important thing. the structures above don't show mitragynin, as mitragynin has a hydroxy attached on position 9 (on top of the phenyl)
and thats , at least in this substance, essential for opioid-activity.
Click to expand...

Doesn't it have a methoxy group rather than a hydroxy?

Also, the Japanese team which has been researching kraktom has suggested that it is 7-hydroxymitragynine that is responsible for the major action of kraktom, even though it is present in much smaller amounts than mitragynine - 7-hydroxymitragynine is apparently 17x more potent than morphine by weight.

http://www.p.chiba-u.ac.jp/lab/seitai/reserches_e.html
 
F&B: I have something to say, but before saying it, I have this:

I am sure you know what Fluoxitine looks like, but I've attached it here as visual aid. If we were to apply the criteria you propose, it plugs in quite nicely on the Fluoxitne molecule - more so than it does with Mitragynine, unless I am looking at it the wrong way (Considering that R1 and R2 aren't too important, as they do not plug into the indoles either) Don't you think? My question is, why is it, then, that Fluoxetine has no opioid activity?

Not trying to dismiss what you're saying... just playing devil's advocate I guess ;) (and actually trying to understand more how your opioid criteria works).

This may seem off topic, but my comment on your Mitragynine proposal will depend on how you answer the above question.
 

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Well, fluoxetine actually is known to have considerable interaction with the opioidergic system, it just isn't clear how directly it affects opioid receptors. The analgesic effect of fluoxetine is signficantly decreased by opioid receptor antagonists, and chronic administration produces opioid-like tolerance.
 
That is very interesting! Do you (or anyone) have backup for this? If so, then I apologize, I stand corrected.


EDIT: Not trying to be an asshole - I'm sure F&B's model has been battered more professionally by many even more knowledgable than me, lol... however, now that I see it, that model also fits into LSD.
 
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Fluoxetine, an opioid? I have some in my drawer and believe me, you dont want to take these!
 
your right, specialspack. its methoxy.
and your also right with 7-hydroxymitragynine.
interestingly, this 7-hydroxy fits into the 4-propionoxy of prodin or the 1-hydroxy of tramadol.
maybe you could oxidise the extracted kratom-alcaloids and get an opioid with the potency of oxymorphon (mixed with some rather inactive by-products) :)
 
Ok... one of you chaps can tell me if this isn't relevant to the thread, and Ill move it...

Saw it and thought it might be of interest.

Life Sci. 2005 Aug 15; [Epub ahead of print]

Inhibitory effect of mitragynine, an analgesic alkaloid from Thai herbal medicine, on neurogenic contraction of the vas deferens.

Matsumoto K, Yamamoto LT, Watanabe K, Yano S, Shan J, Pang PK, Ponglux D, Takayama H, Horie S.

Department of Pharmacology, Faculty of Pharmaceutical Sciences, Josai International University, 1 Gumyo, Togane, Chiba 283-8555, Japan.

The effect of an indole-alkaloid mitragynine isolated from the Thai medicinal herb kratom (Mitragyna speciosa) on neurogenic contraction of smooth muscle was studied in guinea-pig vas deferens. Mitragynine inhibited the contraction of the vas deferens produced by electrical transmural stimulation. On the other hand, mitragynine failed to affect the responses to norepinephrine and ATP. Mitragynine did not reduce KCl-induced contraction in the presence of tetrodotoxin, prazosin and alpha,beta-methylene ATP. Mitragynine inhibited nicotine- or tyramine-induced contraction. By using the patch-clamp technique, mitragynine was found to block T- and L-type Ca(2+) channel currents in N1E-115 neuroblastoma cells. In the Ca(2+) measurement by a fluorescent dye method, mitragynine reduced KCl-induced Ca(2+) influx in neuroblastoma cells. The present results suggest that mitragynine inhibits the vas deferens contraction elicited by nerve stimulation, probably through its blockade of neuronal Ca(2+) channels.
 
There's quite a way between a MOR-specific agonist, an opioid agonist, an opioid, and an opioidergic. My point was that fluoxetine is not a good example, since its interaction with the opioid receptors is unclear. I've recently found this article (about vanlafaxine) :Neurosci Lett. 2004 Jun 3;363(1):25-8. Apparently, naloxone reverses analgesia, but none of the specific opioid receptor antagonists do. Very interesting.
Anyhow - of course fluoxetine isn't euphoric. Antidepressants are screened against "abuse potential", i.e: they are ensured to not be clinically effective to any significant extent.
 
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Yep, I missed the methoxy group off the indole nucleus (apologies).

you just forgot one important thing. the structures above don't show mitragynin, as mitragynin has a hydroxy attached on position 9 (on top of the phenyl)
and thats , at least in this substance, essential for opioid-activity.

the meta-hydroxy is found in many other opioids ( all morphine-relatives, ketobemidon, tramadol, masked as a nitro-group in etonitazen etc) and should be added to your basic structure requirement.
Click to expand...

The m-hydroxy/methoxy isn' essential to activity, or else it's hard to account for the activity of pethedine, MPPP (& all the other prodines), all of the methadone series as well as all the weird and wonderful compounds like dialkylthiambutenes. It generally increases the mu opiod activity, but def isn't essential for activity.
 
It is in some compounds. In the patent by Flick et al tramadol was inactive at producing analgesia with piperidine and/or a bare phenyl ring.

Anyway, the compounds i drew are not that good because it seems that the 7-hydroxy-mitragynine is so much more active as a mu-agonist that it would be ludicrous not to take this into account in the design of novel akaloids.

http://www.google.co.uk/search?hl=en&q=7-hydroxymitragynine&meta=
 
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And what about
J Med Chem. 2005 Jul 28;48(15):4765-71. "Neoclerodane diterpenes as a novel scaffold for mu opioid receptor ligands."
?
 
Well, the full article mainly goes into details of the synthesis procedures and the minutiae of the test results. With regards to the thread's subject, the crux of the matter is this line (which is in the abstract): "We report in this study a nonnitrogenous neoclerodane diterpene with opioid receptor affinity (13) that is an agonist at opioid receptors."

The compound they mention (13) is one where a benzene moiety is conjugated to salvinorin. Actually, the synthesis seems rather simple. Oh, so tempting. They plan on in vivo studies of this compound.

As a side note, I believe this makes the reports of opioid mediated analgesia by Salvia nemorosa all the more interesting. You think my university would mind funding research to see if it contains similarly structured diterpenes?
 
We report in this study a nonnitrogenous neoclerodane diterpene with opioid receptor affinity (13) that is an agonist at opioid receptors
Click to expand...

Just wondering - it doesn't say anything about mu receptors in that title & as salvinorin A is a potent kappa agonist, are you sure the article is about mu agonists?
 
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