Drug info - Herkinorin: Psychedelic Opioid (Salvinorin analog)

[snapper]

This is interesting a little disturbing compound I found mentioned on another forum.

NOVEL ANALGESICS FROM SALVINORIN A
Kevin J. Tidgewell, 1 Wayne W. Harding,1 Robert A. Moyer,2 Chad Groer,2 Christina M. Dersch,3 Richard B. Rothman, 3 Laura M. Bohn, 2 Thomas E. Prisinzano 1* 1The University of Iowa; 2 The Ohio State University College of Medicine; 3IRP, NIDA, NIH, DHHS Baltimore, MD

Salvinorin A, the major active component of the hallucinogenic sage Salvia divinorum, has been shown to be a potent and selective ?-opioid receptor agonist. Previous studies by our lab have shown that derivatives of salvinorin A have activity in tests of nociception in rats. Herkinorin, a previously reported analogue with anti-nociceptive characteristics, was evaluated using a chronic drug administration paradigm and animals were tested using the formalin model for nociception. Herkinorin appears to have an altered mechanism of cellular activation which leads to reduced potential for tolerance. This finding is significant because salvinorin A analogues could represent a class of opioid ligands with altered cellular activation leading to analgesics with reduced potential for abuse. These experiments create an intriguing story about a possible longer acting salvinorin A derivative with ?OR activity and a decreased potential for the development of tolerance. This research is funded by a grant from the National Institute on Drug Abuse (DA 18151).

SWIM thinks that new analgesics derived from salvinorin may also lead to prohibition of salvinorin. This is nonetheless interesting as it seems salvia is spawning a whole new class of analgesics. There is actually a lot of information on this compound. It is also purported to be hallucinogenic, as well as not inducing a tolerance.
Here's another abstract.

J Nat Prod. 2006 Jun 23;69:914-918
Synthesis of Salvinorin A Analogues as Opioid Receptor Probes.
Kevin Tidgewell, Wayne Harding, Anthony Lozama, Howard Cobb, Kushal Shah, Pavitra Kannan, Christina Dersch, Damon Parrish, Jeffrey Deschamps, Richard Rothman, Thomas Prisinzano

Several neoclerodanes, such as salvinorin A (1) and herkinorin (3), have recently been shown to possess opioid receptor activity in vitro and in vivo. To explore the structure-affinity relationships of this interesting class of compounds, we have synthesized a series of analogues from 1 isolated from Salvia divinorum. Here, we report the semisynthesis of neoclerodane diterpenes and their structure-affinity relationships at opioid receptors. This work will allow the further development of novel opioid receptor ligands.

[Bajeda]

If you can find some studies/abstracts on the subject post them in here and I can possibly get pdfs of them when I have time, probably tomorrow.


This looks like it could be an interesting topic to explore.

[snapper]

I'll keep posting them, but the authors are all similar from google. Here is a link with other articles listed :
http://lib.bioinfo.pl/pmid:16792410
Doesn't sound accessible, though the S. polystachya is intriguing...no receptor binding studies, though. Now you can eat your chia seeds and maybe find an active diterpene in the plant material too !

[Ethyl]

Herkinorin a novel mu agonist made from salvia divinorum.



Several neoclerodanes, such as salvinorin A (1) and herkinorin (3), have recently been shown to possess opioid receptor
activity in vitro and in vivo. To explore the structure-affinity relationships of this interesting class of compounds, we
have synthesized a series of analogues from 1 isolated from SalVia diVinorum. Here, we report the semisynthesis of
neoclerodane diterpenes and their structure-affinity relationships at opioid receptors. This work will allow the further
development of novel opioid receptor ligands.

Herkinorin appears to have an altered mechanism of cellular activation different from commom opioids which leads to reduced potential for tolerance. This finding is significant because salvinorin A analogues could represent a class of opioid ligands with altered cellular activation leading to analgesics with reduced potential for abuse or abuse with little/no tolerance.
Salvinorin A has this altered cellular activation too, and it maybe why there's no tolerance with salvia or even a reverse tolerance to salvinorin A/Salvia

This would be the day, a opiate that feels like the first time everytime you use it, no tolerance, so no physical addiction too A junkie dream come true.



Synthesis of Salvinorin A Analogues as Opioid Receptor Probes: (attachment)

Reputation Comments on this post:

	Good find, but you should really add this to the archive.
	Very interesting article, thanks

[bcubed]

Interesting...a little molecular fiddling makes a k-agonist a mu agonist. The only disappointment is the reference cited is far too "respectable" to test on themselves (or at least they won't write about it afterwards).

However, being able to synthesize "super dope" from Salvia would seem to be yet another nail in the coffin for its continuance as a legal drug.

[Zaprenz]

...if it's as potent as salvinorin (but for mu-opioid) that would possibly equate to the potency of fentanyl.

Quite a potential hazard if it is for anyone experimenting.

[bcubed]

Doubleplus smiley-stickers for anyone who can track down the synth. A mitigated-tolerance, non-testable, putatively legal source of mu-opiate agonists that can be grown without much suspicion, even if eventually made illegal...sounds like game, set, match for the prohibitionist set.

[Zaprenz]

...actually thinking about it, if say it was as potent as salvinorin (for mu-opioid though) & didn't have any oral bioavailability (so you can take it as tablet) as is the case with salvinorin that would represent one BIG risk.

Having to smoke a compound that strong the dosing would be incredibly hard to do safely.

If you smoke too much salvinorin - your biggest risk is doing something stupid under the influence but essentially your just going to trip very hard & possibly have a nasty time.

If you accidently smoke too much herkinorin (or equivalent strength mu-opioid) - respiratory depression & overdose.

[does any SWIZ know if salivinorin can be injected? SWIM was under the impression it couldn't be due to complications in dissolving it - another potential problem if solubility varied between potential solvents]

Reputation Comments on this post:

	two good points
	Good points on drawbacks of potential use

[Ethyl]

Yes, looks like we are talking about fentanyl like potency here.
And imagine if one would be able to convert salvinorin into this... salvia contains 2.5mgs per gram of leaves if i'm not wrong, so that would be like 50 to 200 doses from 1 gram of leaves. Certanly one would have a chance to have a lifetime suply of the stuff...

So this could be dangerous like fentanyl, but fentanyl is not dangerous only because of his potency, but because of its respiratory depression wich is greater than tradicional opiates. So we got to wait for the first studys on that.

[jux]

found an interesting article on this promising salvinorin analogue

[top]Opiate research underway

[top]Dave Mosher

Issue date: 9/22/05


A compound which could potentially replace morphine, a widely used narcotic pain-relief drug, began its journey with a drug user in Mexico.

Dr. Laura M. Bohn of Ohio State's Department of Pharmacology said the curious drug user sent a sample of the mint plant species known as Salvia divinorum to Bryan Roth, a biochemist at Case Western Reserve University. The user knew something about both science and drugs, Bohn said, and wanted to know if the active ingredient in the plant was hitting serotonin receptors - a class of receptors responsible for hallucinogenic experiences.

"This plant is related to Salvia in peoples' gardens," Bohn said, "but this particular species grows in Mexico and has been used by Mazatec Indians in vision ceremonies."

Bohn said after some time Roth's group isolated the active compound in the plant which is now known as salvinorin A. During their research, Roth's group also found that the drug had analgesic, or pain-relieving, properties comparable to morphine.

Dr. Thomas Prisinzano, a medicinal chemist at the University of Iowa, then stepped into the picture to study salvinorin A for potential medical uses.

"I got in touch with Dr. Roth after reading his paper and we used chemistry to enhance its pain-relieving properties," Prisinzano said.

Prisinzano said that salvinorin A served as the lead compound, a substance in medicinal chemistry that has favorable effects but is not clinically tested. The result, Prisinzano said, was a chemical called Herkinorin.

Bohn said the compound got its name from Herky the Hawkeye, UI's mascot.

"Of course when it's perfected," Bohn said, "I want it to be called Brutusnorin or Buckinorin."

Bohn was cautious, however, to predict a date for clinical trials but speculated it would be at least 10 years before major publicized progress would be made, if at all.

"At this point it's just a compound," she said.

"Chemists have been working since the 1920s to enhance (morphine's) pain relieving properties and eliminate its addictive properties," Bohn said, "and here in 2005 we're still working on this."

Although the idea of improving natural drugs is nothing new to the scientific world, so far Herkinorin has exhibited exciting properties as a drug comparable to morphine. In her mice models, Bohn said, Herkinorin causes analgesia (pain relief) but does not seem to induce tolerance, cause respiratory problems or even constipation like morphine does.

"With Herkinorin, we found that it produces a response at both the mu and kappa opiod receptors," Prisinzano said.

These receptors are part of neural cells located throughout the body and are responsible for signaling to the brain what many higher organisms perceive as pain.

"The kappa receptor is linked to pain, but it has a few side effects with Herkinorin - mainly hallucinogenic," Prisinzano said.

The compound works more efficiently than morphine by not producing barrestin, a desensitization component that prevents analgesic action at these receptors. By not causing this compound to build up and block the receptor, little or no tolerance develops - a property of great interest to medical chemists like Prisinzano.

"It's something we really haven't addressed yet and need to explore, but it's an interesting development," he said. "And we're in the process of further optimizing the drug. We're excited."

Although the expected date for any drug that may develop from Herkinorin is more than a decade away, Maureen Hanes is also excited about the prospect of a morphine alternative.

Hanes, an OSU graduate and registered nurse at the Ohio State University Medical Center, said she administers morphine almost every day at the hospital.

"I work in the Intensive Care Unit and there are many patients on ventilators because of (morphine's) respiratory side effects," Hanes said. "From that point alone I think it would be very beneficial - we wouldn't have to worry so much about suppressing someone's breathing.

Hanes said that although she does not see morphine-caused constipation as a huge problem during work, she likes the idea of a safer drug to relive pain.

"We're always looking for new and better ways to help our patients," Hanes said, "and it sounds like (Herkinorin) may be safer."

To deal with the legal side of developing a potential drug, Bohn and Prisinzano are working with Ellen Purpus and Andrew Hansen of the OSU Office for Technology Licensing. According to the Purpus and Hansen, applications for patents have already been filed.

"The role of our office is to manage the intellectual property, patenting process, and negotiations of the rights to the patent," Hansen said.

Of the thousands of compounds that are developed for medical use, Hansen said, only a small fraction of drug candidates submitted for testing actually make it to clinical tests.

"It's a long and tortured process, and we're a long way off from actually getting to a drug that could be on the market," Purpus said.

Hansen said that less than 5 percent actually get to human testing and even less enter the market as an FDA-approved drug.

Not only does this process take a great amount of time to complete, Hansen said, but it also cost hundreds of millions of dollars to develop a drug approved for human use.

"The current number being quoted is $800 million," Hansen said of the cost to develop a single drug. "It's not a trivial thing."






jux added 2 Minutes and 55 Seconds later...



Herkinorin Analogues with Differential β-Arrestin-2 Interactions
Kevin Tidgewell,† Chad E. Groer,‡ Wayne W. Harding,† Anthony Lozama,† Matthew Schmidt,† Alfred Marquam,†§ Jessica Hiemstra,† John S. Partilla,△ Christina M. Dersch,△ Richard B. Rothman,△ Laura M. Bohn,‡ and Thomas E. Prisinzano*†§
Division of Medicinal and Natural Products Chemistry, The University of Iowa, Iowa City, Iowa 52242, Departments of Pharmacology and Psychiatry, The Ohio State University College of Medicine, Columbus, Ohio 43210, Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas 66045, and Clinical Psychopharmacology Section, IRP, NIDA, NIH, DHHS, Baltimore, Maryland 21224
Received September 17, 2007


Abstract:
Salvinorin A is a psychoactive natural product that has been found to be a potent and selective κ opioid receptor agonist in vitro and in vivo. The activity of salvinorin A is unusual compared to other opioids such as morphine in that it mediates potent κ opioid receptor signaling yet leads to less receptor downregulation than observed with other κ agonists. Our initial chemical modifications of salvinorin A have yielded one analogue, herkinorin (1c), with high affinity at the μOR. We recently reported that 1c does not promote the recruitment of β-arrestin-2 to the μOR or receptor internalization. Here we describe three new derivatives of 1c (3c, 3f, and 3i) with similar properties and one, benzamide 7b, that promotes recruitment of β-arrestin-2 to the μOR and receptor internalization. When the important role μ opioid receptor regulation plays in determining physiological responsiveness to opioid narcotics is considered, μ opioids derived from salvinorin A may offer a unique template for the development of functionally selective μ opioid receptor–ligands with the ability to produce analgesia while limiting adverse side effects.

(stolen from the interweb)

[Stephenwolf]

don't mean to raise the dead but has anyone heard anything more on the synthesis of this from Salvinorin A? Its been 6 months-ish so plenty of time for more info to have come up. It sounds SO promising. Though Unknown persons are currently more into uppers than downers, they would still love to know if anyone learned of a way to create this?

[TAz69x]

That's quite interesting; being over a few months old I wonder what strides have been made since then.

The largest culprit to tolerance/dependency is the mu-2 receptor, which unfortunately is also the main receptor responsible for the euphoria-mediated results.

Perhaps a tertiary method to inhibit a reaction of mu-2 agonition could inhibit tolerance and dependency? That is, allow mu-2 agonists to bind, but perhaps bind to an additional receptor to inhibit the tolerance/dependency/withdrawal effects of the mu-2 receptor while allowing the euphoria-effects.
I'm sure one day we'll make a discovery that will mitigate the tolerance and dependency of opioids from common usage, and one will be able to remain at a lower level with desired effects! It'd be nice if that happened in OUR lifetime.
(I can't wait til the day when direct neural-stimulation of reward circuits can be accomplished, allowing the press of a button, delivering electrical stimulation allowing euphoria of one's choice ("cocaine-type", "opioid-type", "best euphoria-ever type!", microprocessor-controlled migration and mixture of "types" over an hour-long period, etc.!) through a small machine held in the hand connected to the wires of the brain, attached much like some neural-surgeries, such as the wires "inserted into the brain" through some blindness-affected individuals to an external device to transmit visual information (optical glasses), or the better yet wires directly inserted into the Nucleus Accumbens to battle depression, a clinical trial performed in Europe not too long ago that saw some amazing results!)

Not all is understood yet about tolerance, dependency, and withdrawal symptoms. So it'd be nice to see where this goes, and the synth would be interesting.
It's an interesting molecule, not appearing to be a piperidine-derivative like Fentanyl or Pythidine (meperidine), perhaps slightly complicating the synth from the slightly "easier" piperidine chemistry. Perhaps multi-affinities to the opioid-like receptors beyond mu, kappa, and delta, allowing for some interesting opioid-like activity beyond traditional opioids.

[Ididnotinhale]

Originally Posted by Ethyl

Yes, looks like we are talking about fentanyl like potency here.

So this could be dangerous like fentanyl, but fentanyl is not dangerous only because of his potency, but because of its respiratory depression wich is greater than tradicional opiates. So we got to wait for the first studys on that.

Mg per mg fentanyl is extremely potent and thus dangerous, but it is one of the safest, if not the safest opiate as far as ED50 vs. LD50 goes. Much safer in that sense than morphine, or heroin. This is the main reason why fentanyl has replaced morphine in the O.R.

[Ethyl]

Originally Posted by Ididnotinhale

Mg per mg fentanyl is extremely potent and thus dangerous, but it is one of the safest, if not the safest opiate as far as ED50 vs. LD50 goes. Much safer in that sense than morphine, or heroin. This is the main reason why fentanyl has replaced morphine in the O.R.

That.. but the smaller half-life and everything that comes with that is also a very important reason why fentanyl has replaced morphine in the OR. That leads to a faster recovery time, much faster.. And that makes you leave the hospital faster.. so more money making cause more patients are treated.... And other factors like less histamine production; less expensive; more predictable; etc..; that too have contributed to that replacement..

Ethyl added 2 Minutes and 5 Seconds later...

Originally Posted by Stephenwolf

don't mean to raise the dead but has anyone heard anything more on the synthesis of this from Salvinorin A? Its been 6 months-ish so plenty of time for more info to have come up. It sounds SO promising. Though Unknown persons are currently more into uppers than downers, they would still love to know if anyone learned of a way to create this?

I've eard that the synthesis of herkinorin from salvinorin is extremely easy, whatever that means... But i've eard that its so easy that people are advised not to publish it online cause that would certanly ban salvia where its not banned "yet"..

Ethyl added 2 Minutes and 40 Seconds later...

Originally Posted by TAz69x

Perhaps multi-affinities to the opioid-like receptors beyond mu, kappa, and delta, allowing for some interesting opioid-like activity beyond traditional opioids.

Traditional opioids allready have "multi-affinities" to the opioid and opioid like receptors..

[drug-bot]

Herkinorin is an opioid analgesic that is an analogue of the natural product Salvinorin A. It was discovered in 2005 during structure-activity relationship studies into neoclerodane diterpenes, the family of chemical compounds of which Salvinorin A is a member.[1]
Unlike Salvinorin A which is a selective κ-opioid agonist with no significant μ-opioid receptor affinity, herkinorin is a μ-opioid agonist with more than 100x higher μ-opioid affinity and 50x lower κ-opioid affinity compared to Salvinorin A.[2][3] Herkinorin is a semi-synthetic compound made from Salvinorin B, which is found alongside Salvinorin A or made from Salvinorin A, which is extracted from the plant Salvia divinorum, by deacetylation.[4]
Since it is highly selective for the mu isoform of the opioid receptor, it is likely that herkinorin will be found to produce similar effects to other μ-opioid selective agonists in vivo, such as analgesia and sedation, along with side effects such as nausea, itching, vomiting and respiratory depression which may be harmful or fatal. However unlike most μ-opioid agonists, herkinorin does not promote the recruitment of β-arrestin-2 to the intracellular domain of the μ-opioid receptor, or induce receptor internalisation.[5] This means that herkinorin may not produce tolerance and dependence in the same way as other opioids, although some development of tolerance through other mechanisms has been observed.[6]

[edit] References

1. <LI id=cite_note-0>^ [1]Harding WW, Tidgewell K, Byrd N, Cobb H, Dersch CM, Butelman ER, Rothman RB, Prisinzano TE. "Neoclerodane diterpenes as a novel scaffold for mu opioid receptor ligands." Journal of Medicinal Chemistry. 2005 Jul 28;48(15):4765-71. PMID 16033256 <LI id=cite_note-1>^ [2]Tidgewell K, Harding WW, Lozama A, Cobb H, Shah K, Kannan P, Dersch CM, Parrish D, Deschamps JR, Rothman RB, Prisinzano TE. "Synthesis of salvinorin A analogues as opioid receptor probes." Journal of Natural Products. 2006 Jun;69(6):914-8. PMID 16792410 <LI id=cite_note-2>^ [3]Holden KG, Tidgewell K, Marquam A, Rothman RB, Navarro H, Prisinzano TE. Synthetic studies of neoclerodane diterpenes from Salvia divinorum: Exploration of the 1-position. Bioorganic and Medicinal Chemistry Letters. 2007 Nov 15;17(22):6111-5. PMID 17904842 <LI id=cite_note-3>^ [4]Tidgewell K, Harding WW, Schmidt M, Holden KG, Murry DJ, Prisinzano TE. "A facile method for the preparation of deuterium labeled salvinorin A: synthesis of [2,2,2-2H3]-salvinorin A." Bioorganic and Medicinal Chemistry Letters. 2004; 14: 5099-5102. PMID 15380207 <LI id=cite_note-4>^ [5]Groer CE, Tidgewell K, Moyer RA, Harding WW, Rothman RB, Prisinzano TE, Bohn LM. "An opioid agonist that does not induce μ-opioid receptor--arrestin interactions or receptor internalization." Molecular Pharmacology. 2007 Feb;71(2):549-57. PMID 17090705
2. ^ [6]Xu H, Partilla JS, Wang X, Rutherford JM, Tidgewell K, Prisinzano TE, Bohn LM, Rothman RB. "A comparison of noninternalizing (herkinorin) and internalizing (DAMGO) mu-opioid agonists on cellular markers related to opioid tolerance and dependence." Synapse. 2007 Mar;61(3):166-75. PMID 17152090

this drug has peaked swims interest, imagine a drug that stronglly effects the kappa receptor being manipulated to effect the mu receptors, imagine using salvia to make a potent mu agonist,`we could forgo poppies`and produce potent mu opiates much easier (as poppies only grow in certain climates and it takes enormous amounts to produce a profitable yeild, oh the possibilities, also it says it may not produce tolerance (a junkys dream).

[frederico02]

very interesting that it doesnt cause dependence , ill have a search

[cybergenesis]

An opiates without tolerance! It would be a damn miracle. As far as Swim is concerned the greatest medical breakthrough in the history of mankind.

You should also see MDAN-21

[machine_elf]

Tolerance isn't developed through the secretion of beta arrestin as with other opioids, however, tolerance has been observed through other mechanisms.

Now as far as finding people who have experience with it at home...

Problem being, look at how potent salvinorin A is. I imagine herkinorin has to be assumed this potent at first for the purposes of safety. Now imagine someone at home trying to eyeball micrograms of an mu opioid receptor agonist....

do I smell an overdose?

Probably the reason people aren't being sold this from chemical supply. I agree though, an interesting chemical.

[King_Bee]

Did anyone besides SWIM notice the structure in Post 1 for Sal. A is incorrect?

SWIM wishes it was like the picture in post 1, simple as moving this strand to this spot and adding a benzene ring but the structure in wrong...

If the synthesis for this was publicly available and easy enough, salvia would definitely be made illegal. But is Herkinorin not legal? SWIM believes it is not controlled yet so why not just buy it? Sourcing it may be a little difficult but SWIM is pretty sure our friends in the far East can help us out .