herkinorin

[stvip]

Beta-arrestin is a molecule which is directly involved in tolerance in family of GPCRs. The opioid receptors belong to that family. As expected, there are several studies showing arrestin is intimately related to opioid tolerance, for example:

"... We have previously reported that mice lacking the G protein-coupled receptor regulatory protein, beta-arrestin 2, display profoundly altered morphine responses. beta-Arrestin 2 knockout mice have enhanced and prolonged morphine analgesia with very little morphine tolerance. In this report, we examine whether the side effects of morphine treatment are also augmented in this animal model. Surprisingly, the genetic disruption of opioid receptor regulation, while enhancing and prolonging analgesia, dramatically attenuates the respiratory suppression and acute constipation caused by morphine." J Pharmacol Exp Ther 2005 Sep;314(3):1195-201

Those who have been following studies about salvinorin know that several derivatives have been synthetized which have selective affinity for the Mu-opioid receptor. I recently stumbled upon the following paper (haven't read the full article yet, only the asbtract):

An Opioid Agonist that Does Not Induce Mu Opioid Receptor - Arrestin Interactions or Receptor Internalization.

G protein-coupled receptor desensitization and trafficking are important regulators of opioid receptor signaling that can dictate overall drug responsiveness in vivo. Furthermore, different mu opioid receptor(microOR) ligands can lead to varying degrees of receptor regulation presumably due to distinct structural conformations conferred by agonist binding. For example, morphine binding produces a microOR with low affinity for beta-arrestin proteins and limited receptor internalization whereas enkephalin analogs promote robust trafficking of both beta-arrestins and the receptors. Here, we evaluate microOR trafficking in response to activation by a novel mu-selective agonist derived from the naturally occurring plant product, salvinorin A. Interestingly, this compound, termed herkinorin, does not promote the recruitment of beta-arrestin-2 to the microOR and does not lead to receptor internalization. Moreover, while GRK overexpression can promote morphine-induced beta-arrestin interactions and microOR internalization, such manipulations do not promote herkinorin-induced trafficking. Studies in mice have shown that beta-arrestin-2 plays an important role in the development of morphine-induced tolerance, constipation and respiratory depression. Therefore, drugs that can activate the receptor without recruiting the arrestins may be a promising step in the development of opiate analgesics that distinguish between agonist activity and receptor regulation and may ultimately lead to therapeutics designed to provide pain relief without the adverse side effects normally associated with the opiate narcotics.





An in-vitro study shows that there are cellular markers of tolerance after chronic exposure to herkinorin Synapse 2007 Mar;61(3):166-75
But I still find this pretty exciting and await in vivo study results.

[jacky]

yeah, I have been paying attention to this compound for a little while now. this developement is real exciting.
where this goes is anyones guess

if this compound does get picked up for major research, and the resulting product goes into human research trials, and becomes a pharmaceutical, then I wonder what status salvia divinorum would face?

possibly huge profits for the companys, and another loss for the herbalists?

if outlawing plants is the next big financial plunder,
then we are going to keep playing dirty.

too bad salvia divinorum doesnt grow well from seed.

[Hammilton]

well, it said it's derived from salvinorin A. Thinking of Salvinorin A's structure, do you suppose they used it as a building block, or started from scratch, building something of a similar structure? I can imagine how much fun that was... and how long it took.

Is herkinorin a mu-agonist, or is it just something that prevents beta-arrestin?

Honestly, I don't like Salvia that much to worry about it's legal status. Well, I do, in the way that we'd all be losing something enormously interesting. I mean, I don't use PCP, but i wish it was legal. And being that it's a plant pisses me off more.

If anything, I would think that if they needed Salvinorin A as a precursor, then S. Divinorin would need to be grown- and a lot, I'd suppose. Might ensure it's current legal status. Or they'd criminalize it and grow it in Turkey with the poppies.



This makes me wonder why they decided to use a Salvinorin-derived compound. Is it because tolerance doesn't develop to it? I don't think it does anyway. I've used plenty, and never needed more than a high. But then again, even if I doubled, tripled and 100x'd my dose, odds are I wouldn't notice it much.

Can you imagine the day when euphorigenic, tolerance-free mu-receptor agonists would be available? I'd imagine Heroin would fall by the wayside really fucking quick. I mean, why the fuck would you bother knowing that what 20 bucks today would get you, 300 wouldn't three years from now?

Problem is, Heroin is easily synthed. I mean, super-easily synthed. If there was a compelling argument for legalized drug use, I would imagine that this would be one. No one would ever have to resort to stealing to get a fix.

[Dilaudid]

Hello Hammilton,


well, it said it's derived from salvinorin A. Thinking of Salvinorin A's structure, do you suppose they used it as a building block, or started from scratch, building something of a similar structure? I can imagine how much fun that was... and how long it took.

For now they have to use salvinotin extracted from plants as a precursor because Salvinorin A is expensive as hell if you have to synthetise it (for chemists 8 chiral centers!).
But genetic engineering can change this situation.



Problem is, Heroin is easily synthed. I mean, super-easily synthed. If there was a compelling argument for legalized drug use, I would imagine that this would be one. No one would ever have to resort to stealing to get a fix.

You're right, is en ealyly made drug.

Heroin or your opiate/opioid DOC and b-arestin 2 inhibitors can last for ages with little to no tolerance what a good news for opiophiles and people in pain.

[Paregoric Kid]

does anyone have any information on the synthesis of herkinorin from salvinorin a?

[OxyContinuously]

That is definitely interesting, stvip, and I was wondering if you had a link (or a website or whatever) with the entire paper?

That's something I would like reading about further.

[stvip]

too bad salvia divinorum doesnt grow well from seed.

No need, it propagates very well by clones. I received three cuttings that made it all the way from the US to Israel. They arrived in good shape and 2 out of 3 rooted easily, just stuck them in soil. (unfortunately, the plants succumbed to spider mites).

But yes, these developments are very interesting, but certainly do dim Salvia divinorum's prospects of remaining legal.


well, it said it's derived from salvinorin A. Thinking of Salvinorin A's structure, do you suppose they used it as a building block, or started from scratch, building something of a similar structure?

Salvinorin would be a bitch to synthesize de novo, and there's really no need for it. I'm not sure about herkinorin specifically, but there's a whole family of salvinorin derivatives, with differing affinities to the three opioid receptors (including two with selective high affinity to mu). The chemistry involved is surprisingly simple (involves a reaction which shouldn't seem to work at first glance, but apparently it does). I think further discussion of this topic should not be done in public forums, the legality of the plant is in a precarious position as it is.


Is herkinorin a mu-agonist, or is it just something that prevents beta-arrestin?

It is a MOR agonist, with this (AFAIK) unique property. Please note the caveat about that Synapse article, though.


I've used plenty, and never needed more than a high. But then again, even if I doubled, tripled and 100x'd my dose, odds are I wouldn't notice it much.

You probably aren't using it correctly.


Can you imagine the day when euphorigenic, tolerance-free mu-receptor agonists would be available?

Currently, I believe the most promising candidate is MDAN-21. I wrote about it in the thread "At the end of tunnel", we can discuss it there.


For now they have to use salvinotin extracted from plants as a precursor because Salvinorin A is expensive as hell if you have to synthetise it (for chemists 8 chiral centers!).
But genetic engineering can change this situation.

Genetic engineering will one day change everything. But right now, if you're suggesting genetically engineering bacteria to produce salvinorin, that isn't as simple as you think.


does anyone have any information on the synthesis of herkinorin from salvinorin a?

J. Nat. Prod. 2006 Jun;69(6):914-8.

You should find details about the whole family there.


That is definitely interesting, stvip, and I was wondering if you had a link (or a website or whatever) with the entire paper?

The paper is
Mol. Pharmacol. 2007 Feb;71(2):549-57

My library probably carries it. You can find the abstract in PubMed.

[OxyContinuously]

^^^^^ Hey thanks, stvip. i will definitely be reading that. Thanks for the info!!

later
take it easy
peace


Oxy

[Woowoo]

Saint V knows his stuff folks.... http://www.reallygreattoys.com/images/Chemist.gif
no doubt about it. He should do his own experiments. I can contribute too. I'll sign up as a guinea pig. He can measure its effectiveness by the quality and length of my "woos".

[OxyContinuously]

WooWoo, your fucking signature is hilarious!! I just really looked at it for the first time, and died. I love it!!

[DCBA]

http://img61.imageshack.us/img61/146/salvpj8.png

How can swim convert salvinorin into herkinorin?

[Canis aureus]

Well,

interesting... would like to have a test hit :D

[Papa Verine]

Well,

interesting... would like to have a test hit :D

Yeah, give me some Herkinorin, I'll do a few tests...

[hydrocodonious]

man am i glad this thread got ressurected...this seems really interesting. Im going to look for the article in the library at my university tomorrow. good stuff.

[Hammilton]

So the only difference between Salvinorin A and Herinorin is the addition of the phenyl group?

Is the cyclohexane ring also changed or is that just a mistake missing?

[DCBA]

It only adds the left part of the molecule.

[Hammilton]

So that's just a mistake in the image?

[DCBA]

Yes, it appeared by resizing it.

Later i'll upload the study where i got the image.

[Paregoric Kid]

www.sagewisdom.org has many if not all of the papers on herkinorin and other salvinorin analogs. here are some good ones http://www.sagewisdom.org/tidgewelletal2.pdf
http://www.sagewisdom.org/hardingetal2.pdf (referred to as analog 13 in this paper)
http://www.sagewisdom.org/groeretal.pdf
there are some other mu agonist salvinorin analogs they talk about but I'm pretty sure herkinorin was the strongest one they talked about.

[stvip]

Resorcinol:
(I'm replying here to a post on a different thread, since this thread contains more information):

If you think WIN is more interesting than herkinorin, you are probably unfamiliar with opioid receptor related biology, and GPCRs in general. This discovery is unique. While doing research for a paper I was writing, I came upon an article written by a researcher specializing in GPCRs in which he stated that since beta-arrestin recruitment is a basic part of the receptor activation pathway, screening for GPCR ligands could use a beta-arrestin assay. That's how much it was assumed the two were inextricably linked. So to discover an agonist with this property is extremely interesting. That it has this property and yet induces tolerance is even more interesting (through disappointing from a clinical point of view). Combined with the recent structure determination of GPCRs from the same family (moreover, the prospects for having a crystallographc structure determination soon for the opioid receptor itself are beginning to look good), this could lead to some major future advances in our understanding of the ever so complex opioid receptor and tolerance/dependence mechanisms.

From a clinical perspective, an obvious experiment to try is see whether the fact that different tolerance mechanisms are involved has value in reducing tolerance beyond what is usually achievable with opioid rotation. There's another important practical aspect which is possibly better left unmentioned for now.

[resorcinol]

I actually agree with you from that perspective of viewing the two compounds. I was speaking more about the potential for fun -- I believe WIN 55 might be BETTER THAN weed, perhaps by quite a bit in the euphoria department, while herkinorin is likely just like any other mu agonist feeling wise. The compound's properties relating to GPCR regulation mechanisms are more interesting than a fairly run of the mill cannabinoid (although it is, while not surprising, nonetheless important implication wise that it has nitrogen heteroatoms that can be protonated -- to form water soluble WIN 55 salts. so the implications are further than it just being more fun insuffulated or orally than weed ... it could be INJECTED by everyday people who don't have access to purified THC and would rather not try to rig up a makeshift alcohol solution which could cause vein damage and hurt if the conc is wrong, plus commercial preps of alcohol soluble drugs are probably usually mixed with other compounds to reduce the required alcoholic content... at least I think it's a reasonable assumption. I wonder what a rush from a full agonist at CB1 feels like... maybe it's much more "addictively" euphoric than weed (THC is only a partial agonist after all) ).

[DCBA]

An right now that my 2 loved salvia plants didnt survive last winter.. Its whats heroin does to do a casual gardner, make him more casual..
Must have some more alive, after all its legal and a diviners plant!

[borohydride]

How potent id herkinorin supposed to be? Pure salvanorin is expensive but if the drug were active sub-milligram then it may be worth a punt.

[Woody Bear]

There's a couple of potential problems with herkinorin, firstly it's unstable, and secondly it rapidly breaks down in the body so fast, that injections of it are almost inactive. This might mean that vaporising it could be the only effective route, and if that even worked without it all breaking down, the high would extremely short, probably less than 10 minutes.

An article in: Mol Pharmacol 71:549–557, 2007 (http://www.sagewisdom.org/groeretal.pdf) "An Opioid Agonist that Does Not Induce mu-Opioid Receptor Arrestin Interactions or Receptor Internalization" says:

Herkinorin is subject to degradation; therefore, drugs were produced in small batches, protected from light, and not stored in DMSO or extensively as a powder.


Salvinorin A is biologically active in vivo because it produces hallucinations by its actions at the kappa opioid receptor, yet these effects are very short-lasting (Roth et al., 2002). Systemic injections of herkinorin into mice and rats do not produce analgesic responses; however, peripheral injections do produce localized analgesia that can be blocked by the opioid antagonist naloxone (T.E. Prisinzano and K. Tidgewell, unpublished observations). This may be because herkinorin, like salvinorin A, is susceptible to degradation by esterase, or by other metabolic routes, in vivo and may not be readily available in the central nervous system. Moreover, poor solubility of the compound makes it difficult to administer high concentrations systemically. Further modifications of the herkinorin template are being generated with hopes of identifying a compound with greater stability and solubility than herkinorin.

This makes it sound like herkinorin injected IV would be inactive, and would only work as a local anesthetic if injected S.C., if it works the same in humans as it does in rats.