Sciencemadness Discussion Board

Oxymorphazone how dangerous can be "irreversible" opiate agonist in human brain.

Andres1988 - 9-5-2015 at 01:43


What i understand of it is that once you tried this substance your brain will never be the same and after the effect of this substance passes out about 40 hours later ,you will have tremendous withdrawals which will only pass consuming this substance again... sounds very strange , i didn´t know that there are drugs that can get you to serious dependence from trying it once.

Seems hell scarry ,even more than any other opioid.

diddi - 9-5-2015 at 04:25

it causes dementia like symptoms which can be masked by apparent recovery, but the damage is generally long term. it may possibly be related to dementia onset in later life?

Loptr - 9-5-2015 at 07:13

Wow, that sounds horrible!

That would REALLY screw somebody's life up.

Andres1988 - 9-5-2015 at 08:48

This can be really dangerous substance in wrong hands, as can be sold as new opioid to increase junkies clients to someone, as once consumed there is no way back , going from bad wd to worst wd everytime the effect gone.

Of course ,effects are only knowed in frongs and rats brains , thanks god not in any humans.





[Edited on 9-5-2015 by Andres1988]

[Edited on 9-5-2015 by Andres1988]

Tsjerk - 9-5-2015 at 09:14

Where did you guys find any evidence for use in humans?

Andres1988 - 9-5-2015 at 09:23

Oxymorphazone forms a full on covalent bond with the mu opioid receptor. This bond CANNOT BE REVERSED. I don't care how powerful of an antagonist you have, you can never unseat this agonist from the receptor. The body has to internalize and destroy the receptor and make new ones to end the effects of this drug.

[Edited on 9-5-2015 by Andres1988]

Tsjerk - 9-5-2015 at 11:45

I know what irreversible means... This receptor has a turnover rate of 2-3 days anyway, constantly activated receptors turnover even faster. Hence the half live of 48 hours?

Therefore I think all statements above are an exaggeration of the truth, especially because I still have to find any report of human use. Rats don't seem to show to much different effects than from morphine. (lost the source, sorry!)

Btw; In frogs, the effects of oxymorphazone is reversed by naloxone. Source:

http://www.ncbi.nlm.nih.gov/pubmed/2472540

In vitro it is apparently irriversible, at 5 nM 70% binds, so not even 100%(!) (source below), also don't forget in vivo systems have more tricks up their sleeves, such as rapid endocytosis, exocytosis of new, already present receptors and of course translation of new protein. Besides I probably forget a lot of mechanisms, and a lot are probably not even known.

http://www.ncbi.nlm.nih.gov/pubmed/2436019

But again, could you link to a report of human use of this compound?

[Edited on 9-5-2015 by Tsjerk]

[Edited on 9-5-2015 by Tsjerk]

szuko03 - 9-5-2015 at 12:26

Even though the mass hysteria on sites like "drugs-forum" makes it seem like you die if you take it I wonder how bad it would feel to have a percentage of your opiate receptors die and be recreated by the body? I doubt its "death when you withdrawal" or "forever in withdrawal" Thats not to say that it wouldnt lead to permanent changes that could really mess up someones receptor function it just seems unlikely the body would die from it. That is strictly my opinion based on how resilient human bodys/brains are.

Tsjerk - 9-5-2015 at 12:32

You are also forgetting that these receptors, like all other receptors, "die" every day, over and over, your whole live. With or without this compound you will have your receptors replaced anyway.

In the case of the u-opioid with a turnover of 2-3 days, faster if you use opiates/opioids.

[Edited on 9-5-2015 by Tsjerk]

Andres1988 - 9-5-2015 at 12:58

yes but still its scary , oxymorphazone with a covalent bond to the µ receptor; caveat: causes rapid internalisation of receptors due to chronic overstimulation, much the way that the super-potent fentanil analogues and Bentley's opioids cause rapid, rapid tolerance that makes heroin look like caffeine.

Tsjerk - 9-5-2015 at 13:30

I had a look at the tolerance against fentanyl, but if you mean mild withdrawal after two months continuous use fast tolerance, OK, then yes.

But still, the one time and you're gone statements, seems a bit over the top. Especially because rats and frogs seem to be fine after prolonged exposures.

Andres1988 - 9-5-2015 at 14:17

( Human's body have a very bad property: it grows it's tolerance to opiates/-oids. Just one shot and user have long lasting source of increasing of tolerance. Ok, growth stops fast enough as soon as tolerance becomes high enough to ignore buzz from receptors taken by first dope. But tolerance will not get lower too, even in case of user stopped use any opioids/-ates. Drug tests shows zero opiates in blood as bond molecules just can't cross BBB (blood-brain barrier) in backward direction to be metabolized or removed from body unchanged. All that user get is permanent WDs as endorphines not strong enough to break through tolerance made by first dope. How acute WDs will be depends on first dose.

Let's try to imaging what will junkie do after he had longest buzz that junkie ever had or even ever thought about. Buzz left, WDs came. Guess, what compound will junkie get again? Right, longest, greatest, whatever... oxymorphazone. To get same level of buzz like at last use, junkie should, at least, double dose (source of tolerance to single dose stays in body and not going to leave that body). This time tolerance will grow faster. 3rd shot have to be at least 1st dope + 2nd dope + 1st dope. Nth dope should be at least sum of all previous dopes plus 1st dope. And then comes "end of receptors"... no any other opiates/-oids that can help as oxymorphazone have huge binding activity. Only fentanil will, probably, find couple unbond receptors but thats just a help for an hour... And this last receptor's tolerance will grow too fast if keep hit it each hour... Then starts long, very long rehabilitation time , only endocytosis (the mu receptor itself being removed by the body) removes oxymorphazone from brain. Of cause "end of receptors" can't come, but there will be border and after crossing this border uses will only make WDs a little lighter and with each use this help from uses will become less and less )

As chronically activated opioid receptors are rapidly internalised by β-arrestins, in a similar manner as occurs with non-covalent binding by agonists with extremely high binding affinity such as lofentanil (long lasting analog of fentanyl ), meaning that development of tolerance triggered by receptor over activation is likely to be especially rapide ocurring with as little as a single active dose

So YES, i can bet that can ( 99% will ) get hooked to it, from trying it ONCE .

Thanks god this one is illegal in the US under the analog act !

[Edited on 9-5-2015 by Andres1988]

[Edited on 9-5-2015 by Andres1988]

[Edited on 9-5-2015 by Andres1988]

byko3y - 9-5-2015 at 20:30

Receptors internalization is in fact a more rapidly dropping tolerance (full recovery in 1 week) than morphine induced phosphorylation and others.
The irreversable agonist is destroyed together with the receptor it binds to. http://www.ncbi.nlm.nih.gov/pubmed/7965787

Chemosynthesis - 10-5-2015 at 06:12

Quote: Originally posted by diddi  
it causes dementia like symptoms which can be masked by apparent recovery, but the damage is generally long term. it may possibly be related to dementia onset in later life?
Citation, please. Where are you getting this information?
Quote: Originally posted by Tsjerk  


In vitro it is apparently irriversible, at 5 nM 70% binds, so not even 100%(!) (source below), also don't forget in vivo systems have more tricks up their sleeves, such as rapid endocytosis, exocytosis of new, already present receptors and of course translation of new protein. Besides I probably forget a lot of mechanisms, and a lot are probably not even known.

Very true. As far as Ka or Kd, it is important to note that this is only a single administration snapshat in time, and this will vary with dose and route of administration. It looks like "About 20% of the H-oxymorphazone specific binding is irreversible after reaction at 1 nM ligand concentration [in rat brain isolates.]" PMID:2436019

OP, if you're going to paraphrase wikipedia's oxymorphazone entry, you might as well link to it. And please, stop embarrassing yourself by claiming tolerance is bad and that addiction or dependence is instantaneous and permanent regardless of dosage. You're equally off-base when you try to generalize vague understandings of compartmentalization concepts such as ion trapping and opiate transport with PGP/MDRP2, which happen in contrast to your claims. The substrate you mention doesn't even have an esterified 6-hydroxy group, which is a pretty big deal in terms of BBB compartmentalization to anyone passingly familiar with opiates, so the pertinence is moot. Some of us here have actually worked in very relevant areas to the topic at hand. Tolerance is a very useful mechanism in the human body that just happens to have downsides for some recreational drug users. It's very complex. To claim it's somehow bad as a general rule is so out of touch with reality that you might as well claim homeostasis is evil too, despite clearly being required for life, as that is the overall effect of such feedback mechanisms.

Opiate receptor signaling in the ventral tegmental area is probably the most extensively studied model of receptor tolerance we have, built upon from beta adrenergic receptor regulation experiments, and includes more than just receptor downregulation, but upregulation of effectors such as adenylate cyclase, signal uncoupling and other mechanisms. Clearly, as with any high dwell time agonist in particular, you will get some dose-dependent pharmacodynamic desensitization leading to receptor downregulation and homologous cross-tolerance, but this is hardly some kind of surprise. Whether there is clinical relevancy depends on a number of factors, including the receptor-ligand system's relative activity versus endocytosis.

I would not be surprised to see clinical relevancy in a recreational drug seeker given PMID: 6204757, though this assumes analgesia is an accurate surrogate measure of euphoria and that regulation holds between model organisms in this case, which I don't find unreasonable as a preclinical hypothesis in the absence of more information given the common use of the assay and homology of receptors. There is one huge caveat, though... and that is that there are variations in the c-terminus of these clonal receptors between species, including humans and model organisms such as rats, which could dramatically bias the results of these studies against human clinical applicability. Anyone familiar with receptor trafficking and regulation knows what I mean by this. This is the kind of thing that separates the drug user speculation from the drug researcher: knowledge of mechanistic and paradigmatic limitations and lack of definitive claims without data. I could claim extremely crudely estimate both type A adverse effect and tolerance liability for single administration given systemic plasma concentrations for oxymorphone in Journal of Analytical Toxicology (2009) Vol. 33 pp121-137, the estimated relative potencies between the two drugs in animal models from citations in this thread, then compare CNS compartmentalization models... but this is hardly more than wild intellectual gesticulating and would be met with scorn and derision by anyone expecting scientific discourse.

If the in vitro human affinity is indeed of a covalent enough character to be considered irrreversible to naloxone, this could be problematic depending on the drug potency, as 1) in the event of a high ceiling efficacy, overdose may be difficult to treat as diprenorphine isn't used in humans, though it should be worth noting this may conceivably represent a rescue treatment and 2) relatively low potency may cause addicts with a high established tolerance or induced tachyphylaxis to saturate a percentage of their receptors without a proportional subjective benefit, which would effectively cause increased tolerance and possible receptor regulation side effects of unknown duration. Neither of these will be conducive to a drug-seeker's desire to recreationally activate downstream mesolimbic dopamine neurons through disinhibition, at least in the longterm with option 2. Additionally, there may be ligand-specific quirks to the GRK/arrestin mediated GPCR uncoupling and/or receptor internalization and degradation of human mu opioid receptors that have an impact on tolerance and dependence, including arrestin subtype affinities, which may vary with dose.

Without actual human data there seems little to go on in terms of psychopharmacological speculation for a compound class that's been around since the early 80s, but let's not allow that interfere with all the grandstanding about how one hit and you'll be an addict for life and fry your brain. The relative permanency of such receptor regulatory changes are more at the interface of pharmacology and genetics, typically classified under longterm potentiation or desensitization. Ligand bias in terms of CREB activation and D-FosB will probably have a role in this, and all the effects I have noted may vary with tissue or receptor subtype (i.e. kappa vs. mu). Funny how no one seems concerned about getting permanent diarrhea, yet dopamine depression or "permeanent withdrawals" are touted as fact by the OP, who seems to quite oddly think dosing schedules are completely irrelevant to tolerance.
Quote: Originally posted by byko3y  
Receptors internalization is in fact a more rapidly dropping tolerance (full recovery in 1 week) than morphine induced phosphorylation and others.
The irreversable agonist is destroyed together with the receptor it binds to. http://www.ncbi.nlm.nih.gov/pubmed/7965787

I'm not sure what you mean by this statement as canonical GPCR internalization is mediated by phosphorylation, likely GRK more than PKA in this instance, and can result in either temporary pooling in the endosomes until dephosphorylation and shuttling back to the membrane occurs, or clathrin degradation in lysosomes. FLAG-tagging opioid receptors has shown differences in internalization among opioid agonists, and current work with fluorescent arrestins seems to indicate ligand biased c-terminal conformations that influence phosphorylation efficiency, though clearly dwell time or time-resolved affinity can be expected to play a role in this as well, and distinguishing between the two will be tricky. Arrestin subtype recruited to the GRK phosphorylated receptor does appear to influence eventual fate, evidenced from receptors with chimeric c-termini, and there may potentially also be varying degrees of functionally selective PKA phosphorylation that integrate into this decision.

A topic I am less familiar with is how competitive agonists can sometimes synergistically reduce tolerance when given in combination, and a savvy pharmacotherapist may theoretically be able to leverage this application here, though I see absolutely no benefit to doing so in lieu of more accepted treatments. That said, I think you'd have to be a complete moron to knowingly ingest the title compound, and not only unethical but completely averse to good business practices to try and market this without serious human safety testing.
There's also the whole aspect of diminishing psychological addiction potential by having a long-acting drug, the possibility of forcing a withdrawal which then largely negates the whole aspect of addicts continuing to dose even after heavy tolerance diminishes euphoria because they want to avoid withdrawals. So now you would be balancing an unknown 'gain' in clientele with a known decrease in psychological addiction and reinforcement.

byko3y - 10-5-2015 at 10:27

In fact, there's a lot of people under 20 that are willing to try something new, forbidden and cheap. Like computer dusters or research drugs, that were barely tested on rats. Do you remember the name of a well know wide-spread fentanyl analog? China white. The only reason we don't see oxymorphazone sells is because in China distribution of opiates is punished by death.

Tsjerk - 10-5-2015 at 10:59

Teens in puberty are often willing to do things they shouldn't... I know what china white is, but I don't think either of the former two are relevant in this discussion. You will always find people doing stupid stuff. You know what crocodile is, don't you?
Quote:
The only reason we don't see oxymorphazone sells is because in China distribution of opiates is punished by death.


Death penalty never stopped any substance from being produced or distributed. Nor did it stop any crime from being committed, during the middleages in Europe death penalty was giving for theft... Besides, the synthesis of oxymorphazone is actually pretty easy.

What could be relevant is what Chemosynthesis said, the tachyphylaxis possibly caused by certain compounds. I know that mushrooms (psilocybin) induces very fast tachyphylaxis, and is therefor considered as unlikely to cause dependence. But I could be going to much towards the ""drug user speculation" (as how Chemosynthesis described is so nicely) side on that one.


Edit: with that last note I mean that a real irreversible binding opioid could cause tachyphylaxis, therefore not causing dependence.

[Edited on 10-5-2015 by Tsjerk]

[Edited on 10-5-2015 by Tsjerk]

Chemosynthesis - 10-5-2015 at 11:07

I doubt tachyphylaxis is going to be important for an irreversible compound. Most dose maintenance schedules, particularly for such a long lasting compound or protein/drug moeity will negate this, and tachyphylaxis itself wouldn't resolve the necessity of receptor replacement for homeostatic maintenance on any significant scale.
Tachyphylaxis is very rapid but transient tolerance due to phosphorylation uncoupling of receptors without observed changes in receptor density/total pooling, or in the case of ionotropic channels, often deals with the difference in channel reset vs. closing. Due to the short lived nature of the desensitization, it is difficult to reconcile this with such an effect.


As for the death penalty, China isn't the only mail order locale. India produces quite a few drugs, and former Soviet satellites have often been reported to have distribution of fentanyl derivatives, but if you look at SAR for opioid activity, not only does oxymorphazone have unnecessarily annoying stereo chemistry (from a synthesis perspective), but extraneous pieces of molecule and bridging as well. Much simpler to just synthesize a phenethylpiperidine of known potency, subjective effect, and high yields with current synthetic methods.

[Edited on 10-5-2015 by Chemosynthesis]

Andres1988 - 10-5-2015 at 11:24



An analog under the Federal Analog Act framework can have one additional atom or simple functional group replaced. Adding a hydrazone group to a molecule where there was an oxygen makes it structurally unsimilar to the original compound. Also, one is a reversible opioid agonist and the other is irreversible. Oxymorphone and oxymorphazone are unrelated to each other in the eyes of the law

The names sound similar but the actual structures are different.

So, this one is legal.
[Edited on 10-5-2015 by Andres1988]

[Edited on 10-5-2015 by Andres1988]

Tsjerk - 10-5-2015 at 11:25

Thanks Chemosynthesis for the elaboration on the tachyphylaxis.

But for the synthesis, if you have the compound in question, just with a 6-ketone instead of the N-N=group, you don't have to worry about stereochemistry, do you?

@Andreas1988: I don't know this law nor the compounds it applies to, but the difference between these molecules is still only one functional group

[Edited on 10-5-2015 by Tsjerk]

Chemosynthesis - 10-5-2015 at 11:51

No problem. You have some additional chiral carbons in there that don't deal with the SP2 hybridized hydrazone prior to that point (i.e. 5,14, and the bridge), but once there, correct. In this instance the 3-OH is a possible esterification site, but I didn't want to come out and say that initially.
Quote: Originally posted by Andres1988  
An analog under the Federal Analog Act framework can have one additional atom or simple functional group replaced. Adding a hydrazone group to a molecule where there was an oxygen makes it structurally unsimilar to the original compound. Also, one is a reversible opioid agonist and the other is irreversible. Oxymorphone and oxymorphazone are unrelated to each other in the eyes of the law The names sound similar but the actual structures are different. So, this one is legal. [Edited on 10-5-2015 by Andres1988] [Edited on 10-5-2015 by Andres1988]
You have no idea what you are talking about. The act specifies only that the two be "substantially similar" (just discussing the chemistry) which can be measured in a number of ways. In terms of pharmacology, affinity is not stated in the law, as narcotizing effect is what is important. You can actually read it, as it's public domain... being U.S. law. It is also of questionable applicability overseas, as many countries may choose not to allow their citizens to be prosecuted even for exporting illegal drugs to the U.S., though the DEA does operate overseas.

[Edited on 10-5-2015 by Chemosynthesis]