Akuammine and other Indolic Opioids

[Ham-milton]

This morning while I was getting ready for work, I came across "Akuammine"- an indolic plant alkaloid from Picralima nitida. This particular alkaloid is a mu-antagonist. I haven't been able to find the structures of the other indole alkaloids present in this plant that are agonists. Apparently some are quite potent.

I think the most interesting similarity is the methoxy group in this, and the hydroxy on mitragynine- the oxygen needed for mu affinity (that seems odd, but it's apparently true).

From http://www.globalwarming-awareness2007.wroclaw.pl/en/wiki/Akuammine.html

Akuammine, an indole alkaloid, is the most abundant active alkaloid found in the seeds from the tree Picralima nitida, commonly known as Akuamma.

The dried seeds from this plant are used in traditional medicine throughout West Africa, particularly in Ghana as well as in the Ivory Coast and Nigeria. The seeds are crushed or powdered and taken orally, and are mainly used for the treatment of malaria[1] and diarrhoea, and as a painkiller. An enterprising Ghanaian hospital started manufacturing standardised 250mg capsules of the powdered P. nitida seed, and sold them around the country where they became widely accepted as a safe and effective pain relief product. This then led researchers to try and discover the active component of the seeds.

P. nitida seeds contain a mixture of alkaloids producing antipyretic and antiinflammatory effects along with analgesia.[2][3] Several of these were shown to bind to opioid receptors in vitro, and two compounds, akuammidine and ψ-akuammigine, were found to be potent μ-opioid agonists, although not particularly selective. Surprisingly the main alkaloid from the seeds, akuammine, was found to be an opioid antagonist when tested in vitro and canceled out the effects of the active agonist components.[4]

Given the confirmed activity of the whole seed extract in humans, this makes it likely that akuammine is in fact being metabolised once inside the body to form an active metabolite, in a similar way to how the closely related compound mitragynine is metabolised to the more active 7-hydroxymitragynine.

Akuammine is the main alkaloid found in the seeds, comprising 0.56% of the dried powder, indicating that the 250 mg "Picap Capsules" sold commercially should contain approximately 1.4 mg of akuammine, plus 0.085 mg akuammidine and 0.015 mg ψ-akuammigine. Akuammine is structurally related to both yohimbine and mitragynine, both of which are alkaloid plant products with uses in medicine.

 

[MurphyClox]

Reply to this in "the other" forum.

Murphy

 

[LuxEtVeritas]

For reference:



--------------------------------------------------------------------------------

Yes, that's true. Extracts of the seeds of Picralima nitida (fam. Apocynaceae) have been reported to have opioid analgesic activity. In this investigation, isolated tissue bioassays and radioligand binding assays have been used to determine the opioid activity of five alkaloids--akuammidine, akuammine, akuammicine, akuammigine and pseudoakuammigine--extracted from the seeds of P. nitida. Akuammidine showed a preference for mu-opioid binding sites with Ki values of 0.6, 2.4 and 8.6 microM at mu-, delta- and kappa-opioid binding sites, respectively.

The agonist actions of akuammidine in the mouse-isolated vas deferens were antagonised by naloxone and the mu-opioid receptor selective antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) confirming an action at mu-opioid receptors. In contrast, akuammine also showed highest affinity for mu-opioid binding sites (Ki 0.5 microM) but was an antagonist at mu-opioid receptors with a pK(B) of 5.7 against the selective mu-opioid receptor agonist [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO). Akuammicine has the highest affinity for kappa-opioid binding sites (Ki 0.2 microM) and was a full agonist at kappa-opioid receptors in the guinea pig ileum preparation but a partial kappa-opioid receptor agonist in the vasa deferentia of the mouse and the rabbit.

Akuammigine and pseudoakuammigine showed little or no efficacy in the opioid bioassays. None of the alkaloids had significant activity for opioid receptor-like binding sites (ORL1-binding sites) with Ki values >> 10 microM. These data show that some alkaloids extracted from the medicinal plant P. nitida possess varying degrees of agonist and antagonist activity at opioid receptors but possess neither high affinity nor selectivity for mu-, delta- or kappa-opioid receptors or the ORL1-receptor.

 

[Ham-milton]

How difficult is it to selectively extract these from the plant material?

What concerns me is the affinity for the kappa receptor. it's not nearly as potent as for the mu receptor, but that's still fairly potent, no?

 

[LuxEtVeritas]

well you have to look at the selectivity and indeed it is not that selective over Kappa but selective enough i think to maybe actually make for a real nice effect with the modest kappa activity that may be entailed with the dominant Mu agonism

 

[DCBAe]

And the plant could be used as it is as maintenance treatment program. Taken the plant daily its antagonism would prevent relapsing into other opiates, and if it is as they say that the antagonism is transformed into a agonism in the body, their users would allways experience effects from it. No tolerance because of the antagonist in it.

 

[LuxEtVeritas]

^ i wil be doing research to find that out as I will have the remaining extract as well to play with as i am not sure i buy that conversion to agonist in vivo thing though it makes some sense, but there are also other factors possible

why this was not already pursued and published...well i guess par for the course on a lot of stuff that seems real interesting but open ended to more questions to answer

 

[In the Eyes of God]

What is the pharmacologic effect at the delta receptors? Agonist or antagonist?

Delta antagonists have been shown to prevent respiratory depression (thus lethality) of mu-agonists without impacting analgesia.

A step in the right direction for the perfect opioid (safe, no tolerance, no physical addiction) would be an opioid that was mu-agonist and delta-antagonist, or a combo-porduct of an mu-agonist and a delta-antagonist.

Have any of you tried to search for an extract provider of this plants various alkaloids? Their may very well already be a company supplying its extracted active components.

 

[LuxEtVeritas]

Activity at delta is only specified I think in the paper as potency related but not if agonist, partial agonist, antagonist, or what....

uh, i thought i saw something about someone who knew a guy who had this

 

[MurphyClox]

A step in the right direction for the perfect opioid (safe, no tolerance, no physical addiction) would be an opioid that was mu-agonist and delta-antagonist, or a combo-porduct of an mu-agonist and a delta-antagonist.

...such compounds are known. Examples:
- Pyridomorphinan (a.k.a. SoRI 9409): "Significantly, in contrast to morphine, repeated icv injection of an A90 dose of this compound did not produce any significant antinociceptive tolerance."
- Altrindole (but mu-agonism is weak)
- SoRI 20411
- SoRI 20648
Ref: The AAPS Journal 2006; 8(1), Article 14 (http://www.aapsj.org)

The final lines from that particular ref:
"CONCLUSIONS

The development of potent opioid analgesics devoid of the limiting side effects has been the goal of considerable research efforts. Accumulating evidence strongly support the existence of physical and functional interactions between
the opioid mu and delta receptors. Recent studies using mu agonists along with delta agonists or delta antagonists have provided convincing evidence that there could be clear therapeutic advantages in combining the actions of mu agonists with that of a delta agonist or a delta antagonist. Recent successes in the identification of peptide and nonpeptide ligands possessing
mixed mu agonist/ delta agonist and mu agonist/ delta antagonist profiles, and the encouraging results obtained in studies with these ligands is an exciting development in opioid drug discovery. It is likely that the pursuit of this new approach will lead to novel analgesics superior to those currently available for the treatment of pain.

So, your idea about mixed mu-agonist/delta-antagonist wasn't the worst that I'e heard this week...

Peace! Murphy

 

[LuxEtVeritas]

Well notably then this may be VERY good as both delta, whether ag or antag as it is not known for Akuammidine, would fair well with the solid mu agonism for best overall effect

 

[LuxEtVeritas]

Just to make note as research shall be commencing shortly if 250mg of simply whole seed ground powder at 250mg gave any notable effect with what appears to be only ~1.5MG TOTAL ACTIVES of which it is not even known as yet if the akuammine is an antagonist (as seen in vitro, but counter to in vivo whole seed effect it would appear), an agonist (as speculated to be metabolized to an active in vivo agonist), or simply appreciably not bioavailable (which no one or paper has noted as a possibility but can be the reason) , what then of the active dose of the known agonist akuammidine as pure compound...!!???!!!???!!!!???!!!!!!

 

[George Ainooson]

I am glad to join you in the quest for further research into picralima alkaloids. I have already sent mails to a few members of this forum that I have so much picralima crude extract. What is left now is collaborators to help me employ the latest isolation techniques to isolate the numerous alkaloids present in the crude extract and the the amount of biological work to be done is unlimited. Indeed I am working in the Department of Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences, Kwame Nkrumah University of Science and Techhnology, Kumasi, Ghana in West Africa. This is the very lab that has pioneered research into picralima alkaloids. In fact one of the researchers involved in the investigation into the opiod activity of picralima alkaloids (M. Duwiejua) also works in this same lab.

 

[LuxEtVeritas]

George can you PM me your e-mail as shortly I will be doing some research with Picralima isolates and wish to know what you are currently engaging and hope to share findings...

 

[Jose Jones]

Anyone familiar w/Akuamma and it's alkaloids I could chat with about developing a product?

 

[asecin]

hi, any updates to this please

 

[asecin]

actually this might work better than black cummin for opiate withdrawal, reviewing some subjective experiences on another forum. im still curious and interested to hear people who understand biochemistry a bit more than most to explain its effect and how it can help, thanks

 

[Charles_Voynich]

That's an incredibly interesting structure. It almost has the isoquinuclidene backbone of ibogaine, and that C2 ether bridge is pretty unique.

This morning while I was getting ready for work, I came across "Akuammine"- an indolic plant alkaloid from Picralima nitida. This particular alkaloid is a mu-antagonist. I haven't been able to find the structures of the other indole alkaloids present in this plant that are agonists. Apparently some are quite potent.

I think the most interesting similarity is the methoxy group in this, and the hydroxy on mitragynine- the oxygen needed for mu affinity (that seems odd, but it's apparently true).

Are you talking about the methyl ester?