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herkinorin - mu-opioid salvinorin analogue

Reminisant B

Reminisant B

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http://pubs.acs.org/cgi-bin/sample.cgi/jnprdf/2006/69/i06/pdf/np060094b.pdf

Recently, we described the synthesis of several analogues of 1
that were found to be opioid receptor ligands.11 Among these
compounds described were analogues 2-4. Propionate 2 was found
to have approximately the same affinity for the OR as 1 but was
less potent as an agonist. This work also identified herkinorin (3),
the first neoclerodane diterpene with mu opioid receptor affinity, and
WH-1-32 (4), an analogue slightly more potent than 1 as a OR
agonist.11 Recently, methoxymethyl analogue 516 and carbamate
617 were identified as having affinity for ORs similar to 1.
Interestingly, 5 was found to be a full agonist more potent than 1,
and 6 is a partial agonist at ORs. These observations illustrate
that substitution at the C-2 position can have profound effects on
opioid receptor affinity and activity.
Click to expand...
 
It also sounds potentially lethal:

Making three assumptions [until someone fills in the blanks]:
  • It's as potent as salvinorin (for the mu-opioid)
  • No oral bioavailability (as with salvinorin)
  • Can't easily be injected [Can salvinorin be injected?, I thought it couldn't due to solubility]

A fentanyl strength mu-opioid that HAS to be smoked. That's not asking for trouble at all! 8o Let's just hope no-one does anything too stupid.
 
anyone able to see the reference to see how much more potent 5 is than 1

also 10c and d seem to be superior to 3 as 3 is not all that selective..what is the yield to get Salv B from Salv A as they do not note this as it was noted in a prior study?
 
we had touched on the Salv A agonist here that was just noted in the other thread

anyone have the full text of the below:

Synthesis and in vitro pharmacological studies of new C(2) modified salvinorin A analogues

also this:

Tidgewell, K.; Harding, W. W.; Schmidt, M.; Holden, K. G.; Murry,
D. J.; Prisinzano, T. E. Bioorg. Med. Chem. Lett. 2004, 14, 5099-
5102.

and

J Med Chem. 2005 Jul 28;48(15):4765-71. Links
Neoclerodane diterpenes as a novel scaffold for mu opioid receptor ligands.

if so , TIA
 
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uh, pretty cool....

Molecular Pharmacology Fast Forward
First published on November 7, 2006; DOI: 10.1124/mol.106.028258
An Opioid Agonist that Does Not Induce µ-Opioid Receptor—Arrestin Interactions or Receptor Internalization
C. E. Groer, K. Tidgewell, R. A. Moyer, W. W. Harding, R. B. Rothman, T. E. Prisinzano, and L. M. Bohn
Departments of Pharmacology and Psychiatry, the Ohio State University College of Medicine, Columbus, Ohio (L.M.B., C.E.G., R.A.M.); Division of Medicinal & Natural Products Chemistry, College of Pharmacy, the University of Iowa, Iowa City, Iowa (K.T., W.W.H., T.E.P.); and Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland (R.B.R.)


G protein-coupled receptor desensitization and trafficking are important regulators of opioid receptor signaling that can dictate overall drug responsiveness in vivo. Furthermore, different µ-opioid receptor (µOR) ligands can lead to varying degrees of receptor regulation, presumably because of distinct structural conformations conferred by agonist binding. For example, morphine binding produces a µOR with low affinity for -arrestin proteins and limited receptor internalization, whereas enkephalin analogs promote robust trafficking of both -arrestins and the receptors. Here, we evaluate µOR trafficking in response to activation by a novel µ-selective agonist derived from the naturally occurring plant product, salvinorin A. It is interesting that this compound, termed herkinorin, does not promote the recruitment of -arrestin-2 to the µOR and does not lead to receptor internalization. Moreover, whereas G protein-coupled receptor kinase overexpression can promote morphine-induced -arrestin interactions and µOR internalization, such manipulations do not promote herkinorin-induced trafficking. Studies in mice have shown that -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.

--------------------------------------------------------------------------------
Received June 22, 2006; accepted November 6,
 
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I was reading some stuff on Herkinorin a while back; the people working with it believe it has a much bigger window then morphine analogs before it will shut down a respiratory system. It could turn into a very valuable find if it is a safer alternative to morphine analogs.
 
Reminisant B said:
[*]No oral bioavailability (as with salvinorin)
Click to expand...

Actually, salvinorin A is sublingually bioavailable, just not gastrointestinally. The traditional Mazatec method of using it is to chew quids until effects manifest.
 
luxev's article says it doesn't lead to nearly as much tolerance/dependence. this could be a valuable pharmacological find
 
5-HT2 said:
Actually, salvinorin A is sublingually bioavailable, just not gastrointestinally. The traditional Mazatec method of using it is to chew quids until effects manifest.
Click to expand...

yes though i believe the dose is a few times that of smoked...i forget exactly , but certainly it was higher by a reasonable factor....though indeed a valid method if one cares not to bother with smoking and can not mind using the higher dose

i assume inject 0.05cc acetone is not a big deal perhaps...just speculation so if anyone knows better...but 1mg of Salv A can indeed be solubilized into that amount of Acetone, which at that level i assume is not going to be an issue as our bodies produce it in small amounts anyway
 
Ott found that 100 micrograms to 1 milligram of pure salvinorin A was active sublingually in a solution of acetone or DMSO (Ott 1995)Note; others have found 4 to 10 milligrams or more to be active sublingually in a solution of high-proof ethanol (diluted with 50% hot water, just prior to use).

Yes, Ott actually used DMSO and acetone orally. "Acetone is present in bananas." he quipped when asked about this practice.


is acetone superior subL due to less being needed and thus less[none]swallowed as Ott I assume is reliable here...?
 
What I thought was really interesting about herkinorin was the fact that they've made a minor modification to a selective kappa agonist and produced a selective mu agonist.

This suggests that the mu and kappa receptors aren't that different in shape, and what occurred to me is that there are heaps of selective kappa agonists that have been developed, which are not at all structually similar to any illegal opioids. I wonder how many of those could be tweaked a bit to make a novel mu agonist that doesn't fall under the drug laws.

One that I thought looked particularly interesting was tifluadom http://en.wikipedia.org/wiki/Tifluadom which is a benzodiazepine derivative that is a selective kappa agonist. I wonder if with a bit of modification you could make a compound derived from tifluadom that is both a mu agonist and a GABA-A agonist...no compound with that profile has ever been made as far as I know, and it would be very recreational.
 
mad_scientist said:
What I thought was really interesting about herkinorin was the fact that they've made a minor modification to a selective kappa agonist and produced a selective mu agonist.

This suggests that the mu and kappa receptors aren't that different in shape, and what occurred to me is that there are heaps of selective kappa agonists that have been developed, which are not at all structually similar to any illegal opioids. I wonder how many of those could be tweaked a bit to make a novel mu agonist that doesn't fall under the drug laws.

One that I thought looked particularly interesting was tifluadom http://en.wikipedia.org/wiki/Tifluadom which is a benzodiazepine derivative that is a selective kappa agonist. I wonder if with a bit of modification you could make a compound derived from tifluadom that is both a mu agonist and a GABA-A agonist...no compound with that profile has ever been made as far as I know, and it would be very recreational.
Click to expand...

I dunno how likely the gaba-a agonism would be (since tifluadom isn't one) but a mu-agonist seems likely.

I've seen other papers about benzodiazepine-derived mu-agonists.
 
Paregoric Kid said:
it looks really interesting and it is not an analog of a controlled substance. it would be great if the claims that this does not cause dependency or tolerance hold up. sage wisdom, http://www.sagewisdom.org/, has good papers on this and other mu agonist analogs of salvinorin.
Click to expand...

Thank you for the link =D

i new the site, but did not realize they had all the full texts...NICE!!!!!
 
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