J-113397 near total tolerance prevention!!!

[robojunkie]

Hey all,

I thought you might be interested in this potential future )next few years with Phase III and IV hopefully upcoming. J-113397 is a compound that is an agonist at a set of subreceptors callled the ORL-1 receptors (Opiate like receptor-1) recently discovered around 10 years ago where there purpose wasn't really understood. It' natural ligand is something called nociceptin. Here's the interesting part: Mice that had the gene for this receptor knocked out did not develop any tolerance to standard biomedical addiction protocol (3 days or 7 days continuous and increasing morphine admininstration). A few years later a research group prepared an exogeneous ligand (J-113397) and the researchers found, I believe, (I don't have the paper in front of me, its in the journal Pain, I believe, but a google search will bring you to the relevant paper (published in 2005 or 6, I believe, I can't link it becasue of my uni suscription licensces even with VPN) Main point: some mice were given steady doses of morphine while taking J----, along wiht control mice. They found virtulally no withdrawal syptoms on naloxone administration in this groupl. It's not our holy grail though as the standart J---- dose did not completely attenuate addiction/tolerance amongst mice who were given irregular increasing and lowering doses, though it did have some effect. If this work progresses I know what I will be doing after the phd. Vax, chem, lev, have you heard about these studies? I'm sure you guys probably have access to the literature at your schools.

Oh sorry, there's work in the Pain Journal but this specific article is as follows: The Journal of Pharmocology and Experimental Therapeutics, 2006, 318(1), 262-267. I believe the PI's name is RK Reinscheid. It's pretty interesting, especially considering it seems pretty cutting edge. (I USTFE and no one has mentioned J-113397), Imagine the freaking possilbilities of a total downstream tolerance/addiction modulator.:cool:

[djnarkotik]

Wow that is awesome man. Thanks for sharing. The more we learn about our biology the more we can use this knowledge to help us in our eternal pursuit of happiness. :)

[DCBA]

Some good reading on the subject

http://www.jneurosci.org/cgi/reprint/20/20/7640.pdf

[morphiquet]

just came to mind: the otc antitussive pentoxyverine acts as a orl1-antagonist at high dosages. but it also bears sigma-agonistic and antimuscarinic (M1-antagonist, selective) features at quite lower concentrations, so that might render it useless for the purposes of this thread.

[jopiated]

Hey morph, is this pentoxyverine otc in the states? If so, what is the simple name for it? Thanks!!

[robojunkie]

Yup, that above article was one of the three or four or so I happened upon while researching something entirely different but the phrase "marked tolerance attenuation" I had to look! I think the fact that the other compound just mentioned, pentoxyverine (I'm not familiar with it, I'll have to look it up) has orl-1 antagonist properties as well as sigma (PCP-1/2, aka NMDA calcium ion antagonist) would only help in the cause, although the M-1 antagonism (I forget, that makes it, what a parasympathetic antagonist, like succinylcholine? Or another type, I'm always mixing those up, things like scopolamine, tubocurarine/succinylcholine, muscimol, and so forth, I never remember which are sympathetic ags and antags or parasympathetic ags and antags. But regardless this is not a good thing as you say, none of those categories in my opinion provide anything but fucked up non-euphoric hallucinations or paralysis. Oh yeah, the organophosphates (sarin, vx, etc) are the anti-cholinergics, whereas scopolamine is one that mimics acetylcholine, ie cholinergic.

Nonetheless, I would love to have the time and resources (have most of the resources I imagine, but time is one thing I have very little of. No I'm not dying, I'm just very busy) to synthesize J-113397 as its not that challenging of a prep, I've read it and I've done much longer experimental syntheses in my work (some up to 15 to 20 steps, without "write ups" to use). It'd just be too time consuming right now, though someday I would fucking love to experiment with this protocol. Only bitch is I imagine to obtain optimal effects one would have to dose with this regularly starting with no habit or tolerance. Damn, damn, damn. I wish I knew enough about biology to take an attenuated virus shell and insert the gene recently reported to deactivate the entire tolerance inducing mechanism. That or find a way to trick the brain into thinking its MOR's are unstimulated, while still allowing activation (as in not de-stimulating them with antagonists) with a pure MOR agonist. That or discover the endo-neuronal (as opposed to exo-neuronal, where all the synaptic activity and drugs do their thing) process(es) that manifest opiate tolerance and addiction. Just imagine finding that system, and mapping out the entire genetic sequences responsible for it, ID'ing the relevant enzymes that catabolize/anabolize the receptors, and inhibit it, if not irreversibly.

That would be a Nobel fucking Prize right there! Imagine, all CPers would never have to worry about bickering and bargaining with a dea-intimidated doc and the resultant undermedication, junkies like me could just "use with impunity" and it would eradicate the most central so-called justification the gov and dea use to keep opiates under prohibition (although this is questionable, since it doesn't justify it anyway, if anything it argues against it, and even if then, they'd never give up of their own accord, the change will only happen as families see their kids or their kids' friends unjustly punished/have their lives fucked with or have a dying family member or friend who benefits from pot's effect on AIDS/glaucoma/cancer as well as potentially eating disorders). Oh well, fuck the government, hell at least we have/had a presidential candidate who publicly espouses the desire to re-legalize all drugs, thereby repealing the unconstitutional drug laws as they are now, and the cruel and unusual punishment that is the imprisoning of methadone patients and refusing to maintain them in jail, or offer any kind of adjunct meds to a junky who's been arrested and is CTing.

Woops, wrote this this morning, must have forgot to hit "reply" and such. Oh well, here's a 12 hour old post that isn't...

[Hammilton]

These are the so-called Banyu compounds, right? There's a really good thread discussing them here (http://www.bluelight.ru/vb/showthread.php?t=361115).

And you're right: they are really easy to synth. Considering the potential potency, that's pretty dangerous. There are a lot of substitution patterns that haven't been explored.

best news? They're still totally legal.

However: J-113397 is a u-antagonist.

not gonna find many CPers benefitting from that, will they?

[ryan]

Sorry to bring this back from the dead, but I've been reading more and more about the Nociceptin receptor (ORL-1) and I find it very interesting.

Also, As of Nov. 2008, J-113397 has a wikipedia article..

http://en.wikipedia.org/wiki/J-113,397

Not much info, pretty much all that's stated here, other than it has a clinical application in treating parkinsons.

Any more info regarding this anyone?

[jacky]

very nice...
interesting.

that otc antitussive sounds interesting of itself.