Kratom alkaloids as structural opiods

[C6H6]

J. Med. Chem. 2005, 48, 4765-4771
Neoclerodane Diterpenes as a Novel Scaffold for µ-Opioid Receptor Ligands

Structural modification of salvinorin A, the active component of Salvia divinorum, has resulted in the synthesis of novel neoclerodane diterpenes with opioid receptor affinity and activity. We report in this study a nonnitrogenous neoclerodane diterpene with í opioid receptor affinity (13) that is an agonist at í opioid receptors. This represents the identification of a novel structural class of í opioid receptor agonists.

Obviously, the µ agonist can be made rather simply by hydrolysis of salvinorin A and re-esterification with benzoyl chloride. However, considering how scarce salvinorin A is and the low affinity of 13 for the µ receptor, this doesn't look like the route to new dope.

 

[stvip]

Actually, there was a greek letter mu in front of those 'opioid'. Must've been stripped during cut'n'paste.
Here's the title: "Neoclerodane diterpenes as a novel scaffold for mu opioid receptor ligands." And the same applies to the rest.

Smyth: wouldn't a standard protocol for the identification of this type of compound in plant matter cost peanuts? Isn't this something a university can allow a student to conduct in their spare time? I haven't dirtied (cleaned?) my hands in real laboratory research yet (but soon will), so I'm quite ignorant of the policies involved.

 

[Smyth]

I agree, if the compound was 12 nm then it might just be the next crackpot idea but 13 µm is not gonna cut any ice for something as rare as salvinorium starting material.

 

[stvip]

I agree, if the compound was 12 nm then it might just be the next crackpot idea

It is 12nM (and we are crackpots).

"As shown previously, (1) was found to have high affinity (Ki = 1.9 nM) for kappa receptors"

" (13) resulted in a 47-fold loss of affinity at kappa receptors compared to 1 (Ki = 90 nM vs Ki = 1.9 nM). Surprisingly, this modification resulted in a 25-fold increase in affinity at mu receptors compared to 1 (Ki = 12 nM vs Ki > 1000 nM) and a 5-fold increase in affinity at delta receptors compared to 1 (Ki = 1170 nM vs Ki = 5790 nM)"

If we assume the same bioavailability for salvinorin A and (13), that would require only a 6-fold increase in dose (it should be noted that so far salvinorin has not been found to have any toxicity). I have no idea why you two believe salvinorin is scarce. Not only is plant material very cheap (especially compared to, say, poppy pods), growing 3-4 plants (cuttings are readily available, and its grows well indoors) would yield a continuous supply of more salvinorin than one would know what to do with (extraction of pure salvinorin is also an easy and cheap procedure).
The in vivo study results should be interesting.

 

[morphiquet]

back to topic:
what i wonder is which oxidising agent would fit to yield hydroxymitragynine out of mitragynin

 

[C6H6]

^There's extensive literature and reviews on this. Check Chem Pharm Bull and J Med Chem. Pb(AcO)4 has been used for this purpose.

But a little bird whispered im my ear that 7-OH-mitragynine might soon become avaliable commercially. So you might not need to dirty your hands. I'm just not so sure any more if it's a good idea to put potent opioids out on the RC market. Accidents and overdoses will necessarily follow.

 

[stvip]

But a little bird whispered im my ear that 7-OH-mitragynine might soon become avaliable commercially

That would be obscene. I estimate no more than a month between hydroxymytraginine being available commercially until Mitragyna speciosa and its alkaloids are outlawed in most of the world (US first).

back to topic:
what i wonder is which oxidising agent would fit to yield hydroxymitragynine out of mitragynin

That actually isn't the topic. But I've been wondering that myself. Researchers have used a toxic and expensive reagent to accomplish this efficiently, but I wonder if there is some readily available oxidizing agent capable of performing the conversion, yield being a secondary consideration. Even in very low yields, this could significantly boost the potency of one's kratom.

 

[C6H6]

Discussion of syntheses in not permitted here. It would probably be possible to find a suitable, mild and non-toxic oxidation reagent, but that would require trial-and-error experiments and sophisticated analytical equipment to determine the reaction products.

 

[Smyth]

This idea looks bogus because 3 ester groups in one molecule makes it very difficult for a human to perform the required chemical transformation in-vitro.

 

[C6H6]

Just came across this abstract:

Life Sci. 2004 Mar 12;74(17):2143-55.

Antinociceptive effect of 7-hydroxymitragynine in mice: Discovery of an orally active opioid analgesic from the Thai medicinal herb Mitragyna speciosa.

Matsumoto K, Horie S, Ishikawa H, Takayama H, Aimi N, Ponglux D, Watanabe K.

Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage, Chiba 263-8522, Japan.

Mitragynine is an indole alkaloid isolated from the Thai medicinal plant Mitragyna speciosa. We previously reported the morphine-like action of mitragynine and its related compounds in the in vitro assays. In the present study, we investigated the opioid effects of 7-hydroxymitragynine, which is isolated as its novel constituent, on contraction of isolated ileum, binding of the specific ligands to opioid receptors and nociceptive stimuli in mice. In guinea-pig ileum, 7-hydroxymitragynine inhibited electrically induced contraction through the opioid receptors. Receptor-binding assays revealed that 7-hydroxymitragynine has a higher affinity for micro-opioid receptors relative to the other opioid receptors. Administration of 7-hydroxymitragynine (2.5-10 mg/kg, s.c.) induced dose-dependent antinociceptive effects in tail-flick and hot-plate tests in mice. Its effect was more potent than that of morphine in both tests. When orally administered, 7-hydroxymitragynine (5-10 mg/kg) showed potent antinociceptive activities in tail-flick and hot-plate tests. In contrast, only weak antinociception was observed in the case of oral administration of morphine at a dose of 20 mg/kg. It was found that 7-hydroxymitragynine is a novel opioid agonist that is structurally different from the other opioid agonists, and has potent analgesic activity when orally administered.

PMID: 14969718
http://www.ncbi.nlm.nih.gov/entrez/...e&db=pubmed&dopt=Abstract&list_uids==14969718

Unfortunatly, I don't have access to the full paper (somebody could post it?). However, according to this paper (full text online free) the potencies are:

Mitragynine = 0.26 x morphine
7-Hydroxymitragynine (7-OHM) = 10.71 x morphine
Mitragynine pseudoindoxyl (MPI) = 30.67 x morphine

If the analgesic dose of 7-OHM in the mouse is 2.5-10 mg/kg s.c., it is certainly not 10x as potent as morphine, since the analgesic dose of morphine in the mouse is usually around 5mg/kg s.c., depending on the test, the strain of mouse etc.

So 7-OHM might not fulfill the expectations regarding potency. If 7-OHM is pharmacologically disappointing, it can be easily converted into the even more potent MPI by base-catalyzed rearrangement.

I could also see the MPI as having higher bioavailability and better metabolic stability compared to 7-OHM. The imine-nitrogen in 7-OHM is not a great asset either.

 

[scarmani]

It would appear from the references that 7-OHM possesses high oral bioavailability relative to its parenteral bioavailability, whereas morphine has poor oral bioavailability relative to its parenteral bioavailability. Thus I would suspect (though to my knowledge this has not yet been confirmed in humans) that 7-OHM would be significantly more potent than morphine p.o.

The estimates of potency factors for 7-OHM and MPI are based on in vitro assays (guinea-pig ileum, mouse vas deferens), and competitive binding assays. By these measures, MPI looks like a quite potent opioid.

"Mitragynine pseudoindoxyl, an oxidative derivative of mitragynine, was found to show potent opioid agonistic activity in the guinea pig ileum and in mouse vas deferens. The potency of MPI on mu-opioid receptors in the guinea pig ileum was about 100- and 20-fold higher than that of mitragynine and morphine, respectively. Additionally, its potency on delta-opioid receptors in mouse vas deferens was about 700- and 35-fold higher than that of mitragynine and morphine, respectively... "

PKi values:
morphine: 8.46 @ mu, 6.38 @ delta, 6.33 @ kappa (98.5%, 0.8%, 0.7% )
mitragynine: 8.14 @ mu, 7.22 @ delta, 5.96 @ kappa (88.7%, 10.7%, 0.6% )
MPI: 10.06 @ mu , 8.52 @ delta, 7.10 @ kappa (97.1%, 2.8%, 0.1% )
7-OHM: 7.87 @ mu, 6.81 @ delta, 6.91 @ kappa (83.3%, 6.6%, 10.1% )

However, when tested in vivo, MPI did not have the expected antinociceptive potency and appears to be metabolicly labile even when injected directly into the brain of the mouse:

"Mitragynine pseudoindoxyl, administered by intracerebroventricular (icv) injections, showed antinociceptive effects in the tail flick test in mice. Its effect reached a maximum at about 15-45 min after the injection. The effect of mitragynine pseudoindoxyl is less potent than that of morphine... Mitragynine pseudoindoxyl exhibited less potent analgesic activity than morphine, despite very high opioid activity in isolated guinea pig ileum test. We speculate that the low analgesic activity of mitragynine pseudoindoxyl results from the instability of the compound in the brain."


Antinociceptive effect of 7-hydroxymitragynine in mice: Discovery of an orally active opioid analgesic from the Thai medicinal herb Mitragyna speciosa.
Kenjiro Matsumoto, Syunji Horie, Hayato Ishikawa, Hiromitsu Takayama, Norio Aimi, Dhavadee Ponglux, Kazuo Watanabe
Life Sci. 74(17), 2143-2155 (2004)
http://tinyurl.com/bbax6

Opioid receptor agonistic characteristics of mitragynine pseudoindoxyl in comparison with mitragynine derived from Thai medicinal plant Mitragyna speciosa
Leonardo T. Yamamoto, Syunji Horie, Hiromitsu Takayama, Norio Aimi, Shin-ichiro Sakai, Shingo Yano, Jie Shan, Peter K. T. Pang, Dhavadee Ponglux, Kazuo Watanabe
General Pharmacology 33, 73–81 (1999)
http://tinyurl.com/8v2uv

Studies on the Synthesis and Opioid Agonistic Activities of Mitragynine-Related Indole Alkaloids: Discovery of Opioid Agonists Structurally Different from Other Opioid Ligands
Hiromitsu Takayama, Hayato Ishikawa, Mika Kurihara, Mariko Kitajima, Norio Aimi, Dhavadee Ponglux, Fumi Koyama, Kenjiro Matsumoto, Tomoyuki Moriyama, Leonard T. Yamamoto, Kazuo Watanabe, Toshihiko Murayama, and Syunji Horie
J. Med. Chem. 45(9), 1949-1956 (2002)
http://tinyurl.com/aaeu6


7-OHM on the other hand, despite weaker binding to mu receptors than morphine, appears to exhibit surprisingly good potency presumably because of its superior bioavailability by an oral route, and rapid-acting nature:

"Antinociceptive effects of 7-hydroxymitragynine and morphine were compared in acute thermal pain tests in mice... In the tail-flick test, the Maximum Possible Effect value of 7-hydroxymitragynine (5 mg/kg, s.c.) reached 100% between 15–30 min after its administration. On the other hand, the maximum MPE value of morphine (5 mg/kg, s.c.) was only about 69%, at 45 min after its administration... The results about oral administration are noteworthy in tail-flick and hot-plate tests... In the tail-flick test, 7-hydroxymitragynine (2.5–10 mg/kg, p.o.)showed a dose-dependent inhibition of pain response. The MPE value of 7-hydroxymitragynine (10 mg/kg, p.o.) reached 100% between 15–30 min after its administration, and a significant antinociceptive effect lasted for 90 min. On the contrary, the MPE value of morphine (20 mg/kg, p.o.) was only about 49% at 45 min after administration."

From the Life Sci reference, it looks like 7-OHM would be expected to be about 6-fold more potent taken orally than morphine taken orally, and perhaps 2-fold more potent taken subcutaneously than morphine taken subcutaneously. It also seems as though it would produce effects faster than morphine, but that the effects would last about as long.

To my knowledge, none of this has yet been confirmed in humans. (Except to the extent that 7-hydroxymitragynine is the main compound responsible for effects from Kratom.)


=================


About the ethics of putting potent opioids in the hands of people:

Putting potent opioids in the hands of people is defensible only in the context of human freedom, which includes the freedom to make ruinous or deadly mistakes.

Some societies, for example, believe strongly in the right of individuals to bear arms (own guns). This despite the fact that guns are weapons; their only function is to kill or harm living things.

In these societies, there is the belief that every individual has an innate, God-given right to kill and harm living things if they deem it appropriate or necessary under the circumstances. A belief, in other words, that each individual has free will, rational faculties, and is fundamentally responsible for his or her own actions. That these are endowed upon the individual by a divine authority, and therefore no mortal authority has the right to strip those freedoms away from the individual, even if those freedoms include the freedom to threaten to harm or kill.

Does such a belief make any sense? Perhaps, perhaps not... it depends on your view of human nature and what "freedom" truly means as an ideal. But, if you are willing to believe that people have been endowed with a God-given right to bear weapons, which can be used for nothing other than the sole function of killing or harming living things, then it makes no sense to believe that people must be prevented from the freedom and responsibility of access to things which merely COULD kill or harm.

Personally I am an atheist, and believe that people are biological machines with no free will. I see little or no difference between french fries, cigarettes, automobiles and 7-OHM. They all are addictive, and the use of the first three certainly each kill thousands or tens of thousands of people every year. Who is presumptuous enough to decide that people should not be permitted access to french fries, or cigarettes, or automobiles?

Well, at least that is what I suppose the french fry sellers, cigarette pushers and automobile makers tell themselves to get to sleep.

 

[stvip]

This idea looks bogus because 3 ester groups in one molecule makes it very difficult for a human to perform the required chemical transformation in-vitro.

I don't understand this statement, for this is precisely what has been done (see the paper). I think finding a low-yielding but easy to use and obtain reagent is feasible, but nothing specific comes to mind (but then, I am not a chemist).

With regards to scarmani's post on human freedom, I agree, with two exceptions: I protest that sugar isn't first in the list of legal but destructive addictive substances, and that there should a clear distinction between items harmful to oneself (in which case it should be noted that unlike an unhealthy diet, opioids do not necessarily cause any harm) and those which might be directly harmful to others (especially firearms, since that is their sole purpose).

However, de facto, making 7-OH-hydromitragynine commercially available will only have negative consequences for all conernced, with the exception of the vendor and possibly the few people who will have a short window of opportunity to purchase it before it is outlawed. Widespread growing and harvesting of the plant would have allowed anyone interested to enjoy this legal opioid, and the DEA didn't seem concerned in its Microgram mention of kratom commerce.
The reason for my alarm (and indeed, disgust) is not due to abstract principles, but rather the concrete consequences to be incurred.

What is needed is identifying diverse sources of opioids, so that the legislative and enforcement system would be overwhelmed (much like is the case with tryptamine psychedelics, where there are for too many common carriers of DMT and related compounds). Hence my interest in the potential of using opioid agonists from Salvia divinorum and nemorosa, as well as several other plants I'm investigating (I have compiled a list of leads, if anyone is interested)

 

[C6H6]

Well, sometimes theoretical considerations and practical experiments yield quite opposite results. That's why experiments are done.

Talking about opioids, I just realized that the antagonist naloxone can be converted into either oxymorphone or the even more potent N-phenethyl-N-noroxymorphone in a high yielding (>90%), one-pot, two-step process. Might be someting to ponder upon for chemically educated opioid lovers.

 

[Smyth]

When I first saw this idea I was like 'woah'. Then when I saw it again and saw the three ester groups I thought 'naw'. Now I am at the point of actually thinking that is in in fact a good idea.

Obviously, the µ agonist can be made rather simply by hydrolysis of salvinorin A and re-esterification with benzoyl chloride.

Polyketide Synthase is the type of thing that can be manipulated by genetic engineers. I definately would like to think that there is potential here. If somebody can post the full document then I think this would be really useful.

 

[morphiquet]

@stvip: surely i'd be very interested in your list of opioid plants, i can't get enough info about opioids in general