Opioids of the Future (2011) ver. 2

[psykoman]

MOD'S NOTE:

You may have noticed the previous thread is gone. This is because it was full of asinine rules-breaking chatter that contributed nothing of value. I have moved here the handful of posts I thought had some substance in them. If your post did not make it, don't take it personally - it may have simply been you replying to a deleted post. Or it may have been - in which case I welcome you to contribute within the following guidelines:

What this thread IS NOT about:

- This thread is NOT about exchanging patents that deal with the synthesis of powerful opioids.

- This thread is NOT about arguing why Salvinorin-A is so expensive in Sigma-Aldrich's catalogue.

- This thread is NOT about discussing ANY chemistry OR prices.


What this thread IS about:

- This thread IS about sharing personal experiences with novel opioids.

- This thread IS about speculating on the PHARMACOLOGY (n.b.: not chemistry) of novel opioids.

- This thread IS about giving HARM REDUCTION advice to people who post asking about novel opioids they intend to ingest.


Also note that I'm not being an asshole - I am intentionally making the opioids threads far more restrictive on this forum for reasons we are all well aware of.

Consider this post your informal warning. Thanks for respecting this forum and its rules. Jam


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since the following RC opaits are now sum what avalible i would like to kno if any of you in the kno if any of these would be good for stopping a herion rattale or just general recreational use. - sorry if this is in the wrong place.

they are the following chemicals.

nor-Binaltorphimine
Useful References
Endoh et al (1992) Nor-binaltorphimine: a potent and selective k-opioid receptor antagonist with long-lasting activity in vivo. Arch Int Pharmacodyn Ther. 316:30-42.

Takemori et al (1988) Nor-binaltorphimine, a highly selective k-opioid antagonist in analgesic and receptor binding assays. J Pharmacol Exp Ther. 1246:255-8.

Portoghese et al (1987) Binaltorphimine and nor-binaltorphimine, potent and selective k-opioid receptor antagonists. Life Sci. 40:1287-92.



Dynorphin A
Biological Description
Endogenous potent κ agonist. Analgesic effects in vivo and involved in cardiovascular regulation.





Herkinorin
Biological Description
Selective μ opioid receptor agonist derived from the plant product, salvinorin A (Asc-084). Does not promote the recruitment of beta-arrestin-2 or lead to receptor internalization



Naloxone hydrochloride am sure this is the one that reverses effects tho



Nociceptin


Biological Description
Endogenous ligand for the opioid-like receptor, ORL1


they also have Salvinorin A
did not that kno it was an opiods or is it just spelt similar.

anyone kno anything about the above chems?


psyko

 

[SKL]

Sad but true, you can tell the brief periods that legit RC opioids are circling because people with drug forum accounts start dying. None of the above really fit the bill nor does much of the chemical masturbation that goes on, but there are some compounds out there that are truly terrifying. None of them come from whatever website you copied that off of, though.

 

[Deleted member 170540]

Kappa antagonists have an antidepressant effect, but they are probably not euphoric.

See http://www.aapsj.org/articles/aapsj0703/aapsj070371/aapsj070371.pdf

...Another exciting area where kappa opioid antagonists are being explored as therapeutic agent is their potential use in the treatment of depression. The kappa opioid antagonists norBNI i.c.v., GNTI i.c.v., and ANTI intraperitoneal (i.p.) all displayed antidepressant-like activity in the forced swim test...

 

[adder]

In the last phase of my experiments with various opioids I focused on kappa antagonists and/or delta agonists/partial agonists (anyway, this is just a small part). Those drugs have big potential for being good antidepressants. Anyway, in most cases there's always some side effect that makes the drug unsuitable even for trying but for me it's just that (S)(N)(D)RIs are good for making money, it doesn't matter for big pharmaceutical companies if there are better drugs out there as long as those (S)(N)(D)RIs are a temporary solution and it's good for making money. So why change it?

I couldn't and I can't jump on any of these compounds as I'm addicted and I'm on methadone. But there was a time I was on buprenorphine for over 2 months. Buprenorphine is a kappa antagonist. I'll ignore the fact it didn't work too good as a maintenance drug unless on >16mg. But it also made me feel alright with the rest. Methadone takes away withdrawal but it doesn't help my depressive episodes. Buprenorphine did stabilize me and I saw the world in colors.

 

[StaySedated]

kappa agonists aren't euphoric. i've got to say that none of the drugs you listed look worthwhile.

 

[adder]

kappa agonists aren't euphoric. i've got to say that none of the drugs you listed look worthwhile.

I didn't know this thread was dedicated only to euphoric opioid agonists. Well, if it were, I'd have something to say about 6-alkyl ethers of 4,5-epoxymorphinans, 3- and 6-esters of 4,5-epoxymorphinans, 14-substituted and N-substituted 4,5-epoxymorphinans, morphinans, benzomorphans; various 4-phenylpiperidines, fentanyl with 4-anilinopiperidines and 3,3-diphenylpropylamines groups of analgesics etc. That's exactly what's the most interesting to me in this field if we're talking about agonists.

But are those really RC opioids?* Their SAR, mode of action and synthetic routes to them and their antipodes are well described in literature. As you know synthesis discussion is not allowed here so let's discuss experiences with opioids you can come along on streets? I don't think that was the purpose of this topic but I may be wrong.8)

*I mean you won't get any pentamorphone, heterocodeine or 14-propoxyhydromorphone from some vendors. The thing with most people who use opioids is all they care for is the rush and they aren't interested in neuroscience...

 

[Nagelfar]

The thing with most people who use opioids is all they care for is the rush and they aren't interested in neuroscience...

True but not to be expected anymore than expecting a professional basketball player to be interested in classical physics.

 

[adder]

True but not to be expected anymore than expecting a professional basketball player to be interested in classical physics.

Right, it's rather a coincidence there are people on these forums who both had/have some experience with (ab)using psychoactive drugs and possess a lot of knowledge in various branches of neuroscience, pharmacology, and chemistry. Or drug abuse problem concerns all people no matter what they do for living, what they believe in etc. I guess the latter is true...

 

[adder]

Just like all κ-opioid antagonists and δ-opioid (partial) agonists. Nevertheless every drug I checked hadn't gotten to some real research phase because of side effects. Also, think of cyclazocine, it was researched as a medication for bipolar disorder (not only) but it was aborted because of side effects and at the time it was researched and tried in human, it showed quite good effects. But who would start it all over again if it had been discontinued long time ago? And the reason was probably because of sigma agonism. Who knows? Maybe some problems with signaling there or with NMDA channel plays a key role in mood changes. Psychiatry as medicine specialization is now probably the one that hasn't evolved much during like last 30 or 40 years give or take.

It all seems like big pharmaceutic companies prefer the present situation when the market is flooded by nasty (S)(N)(D)RIs that doesn't help in the long term but sometimes even worsen things. Also psychiatrists don't care mostly either, they just change medications and they don't give a damn if a patient can pay for these ridiculously expensive pills or not. First I was diagnosed wrongly, one day I got a severe episode of mania because of paroxetine (and the dose of it was raised and raised because it was helping worse and worse for my depression). The final is another psychiatrist now prescribes me again paroxetine among other pills. I simply lost faith they could change anything. I take what I have to take and I learned to live with my BPD though it's often not easy. I don't even buy drugs like paroxetine or mood stabilizers etc. I've got plenty of them at home anyway...

 

[pofacedhoe]

the only drug that helped me with my bipolar depression was tramadol, it was a godsend. since i came off it i haven't had a really big up or down swing at all. cutting out caffeine has also improved things beyond words. citalopram made it a lot worse

 

[adder]

2-phenylethyl, 2-(2-furyl)ethyl, 2-(2-thienyl)ethyl all cause an increase in MOR affinity. Anyway, the parent compound is levorphanol. Claims it may be less addictive probably arise from the fact it doesn't produce any kind of rush, yet it hits within a minute or two injected intravenously and for people abusing opioids it has a big upside, it provides huge euphoria for 10 or more hours. As a painkiller it also proves to be better than classical opioids as its pharmacodynamics are a bit different, apart from acting on opioid receptors, it's got more potential on sigma receptors, it blocks NMDA channel, and it blocks 5-HT and NA reuptakes. Yet, they withdrew it from the market.

 

[titstypedthis]

can there be an opioid thats too good?

i say no, but im not the fda

 

[adder]

What do you mean by that? Deducing from your mentioning FDA it refers to recreational properties of opioids. I guess there's no such a term like "too good" when we're talking about any abusable drugs. Well, "good" and "bad" are already very subjective, there are drugs that are "moderately abusable", "highly abusable" etc. but calling a drug good is simply stating it gives you pleasurable effects.

In terms of pain-killing properties, however, there are many good opioids not used in medicine for unknown reasons. Levorphanol is a good example. The parenteral to oral ratio is much better than hydromorphone's, oxymorphone's, morphine's, or heroin's (2:1), it's effective against a wider spectrum of pain types, it works longer. Finally, it doesn't produce instant rush when injected intravenously and that's an upside for physicians, right? So why has it been withdrawn? Sure, it would get a lot of "fans", let's be honest, its pain-killing effects last similarly long as methadone's (not to be confused with methdone ability to prevent withdrawal) but it produces far more euphoria. But if anyone can name an opioid without mu-agonistic properties that's really useful, please name it. Mostly only drugs like morphine, hydrocodone, oxycodone, or hydromorphone are prescribed. In severe pain opioids like methadone or buprenorphine are treated as a last resort painkillers when a patient doesn't respond well (anymore) to the drug (s)he's been given.

 

[fencamfamine]

2-phenylethyl, 2-(2-furyl)ethyl, 2-(2-thienyl)ethyl all cause an increase in MOR affinity. Anyway, the parent compound is levorphanol. Claims it may be less addictive probably arise from the fact it doesn't produce any kind of rush, yet it hits within a minute or two injected intravenously and for people abusing opioids it has a big upside, it provides huge euphoria for 10 or more hours. As a painkiller it also proves to be better than classical opioids as its pharmacodynamics are a bit different, apart from acting on opioid receptors, it's got more potential on sigma receptors, it blocks NMDA channel, and it blocks 5-HT and NA reuptakes. Yet, they withdrew it from the market.

I think the N-phenyethyl made stage II, but none of them ever went mainstream, AFAIK. The problem was the duration didn't match up to levorphanol & it had less NMDA activity - it lost the market levorphanol was aimed at.

The big advantage was supposed to be the huge TI, but since TI wasn't a stated issue, they were answering the wrong question. Ideally, doctors want an analgesic that does not cause too much euphoria.

One oversight that may just get this class looked at again is that it appears to cause far less tachyphylaxis than other 'super potent' MOR agonists. That may see it's return (then again, the Chinese already seem to be finding less favour with DHE).

 

[adder]

i was thinking about etonitazene and the bloke who got addicted and killed hisself because of the WD's.

i mean if that was introduced in medicine, how would you bring someone back down from maintenance with that?

One could have just simply taper off to the point where substitution was possible. However, as I know it's hard with most often used opioids...

1. Switch to something different in structure (to counteract cross-tolerance, with etonitazene being a benzimidazole deritivative it shouldn't be a problem) but yet strong enough.

2. Repeat it until substitution with methadone/buprenorphine is possible. Buprenorphine is actually a very strong analgesic on a weight basis. And didehydrobuprenorphine is actually twice as potent.

I think the N-phenyethyl made stage II, but none of them ever went mainstream, AFAIK. The problem was the duration didn't match up to levorphanol & it had less NMDA activity - it lost the market levorphanol was aimed at.

The big advantage was supposed to be the huge TI, but since TI wasn't a stated issue, they were answering the wrong question. Ideally, doctors want an analgesic that does not cause too much euphoria.

One oversight that may just get this class looked at again is that it appears to cause far less tachyphylaxis than other 'super potent' MOR agonists. That may see it's return (then again, the Chinese already seem to be finding less favour with DHE).

To be honest I don't expect phenomorphan to be introduced on the market (just like I don't see the point of N-phenethylnormorphine coming). Stronger or more potent isn't equal to better no matter if we talk about pain-killing value or recreational value. I myself never favored N-derived tens times potent (4,5-epoxy)morphinans. Maybe only with benzomorphans one would take phenazocine having syringes with metazocine, cyclazocine, pentazocine, and phenazocine to choose one from.

The only thing I wonder is why levorphanol was withdrawn. I know reports of people who used to be prescribed it for pain and they really praised it. I have never been in such pain needing a strong painkiller but I also praised racemorphan/levorphanol for its recreational value.

Ah, despite my scientific interest in opioids sometimes such discussions make no good to me as I've been on methadone for over a year now and all they cause are surges of cravings (I can't take high enough doses of methadone not to care about).

Why get so hooked on the phenanthracene class?

For black market it's simple, they come from natural source = less cost. And for scientific purposes, well to be honest with you playing around with a morphine compound leads to a lot of interesting opioids. Right, maybe one has to be a "connoisseur", "taster" of opioids to tell apart some 14-alkyloxy derivatives of 4,5-epoxy-7,8-dihydromorphinans. Anyway, I used to be obsessed myself with getting to know the difference in "taste" between plain heroin and nicomorphine. A strange mix of a scientist soul and an addict soul, it seems. Then at the end of the day it didn't matter if you had some 14-amino derivative of hydromorphone or an 3,6-ester of morphine or DHM.

 

[fencamfamine]

Many countries seem to retain 1 MOR+/NMDA- agent for medical use & levorphanol is supposed to be just about the best of this class but it appears that the addictive liability may be higher than some other opioids. The only reason for the N-phenylethyl was to reduce costs (this was very old research, Grewe synthesis-era).

The benzomorphans didn't seem to have a great deal to offer & they seem more complex/costly to make than many other classes & the side-effects profile seems to be more variable than phenanthracene class (KOR and such) which reduced their flexibility.

I mentioned this before, but here is the reference:

J. Med. Chem. 2007, 50, 3765-3776

Synthesis and Structure-Activity Relationships of a Potent MOR-Agonist DOR-Antagonist and an Exceedingly Potent Antinociceptive in the Enantiomeric C9-Substituted 5-(3-Hydroxyphenyl)-N-phenylethylmorphan Series

The above was an attempt to design a potent (>x500 morphine) analgesic with a lower dependence liability. I suspect that all they succeeded in making was an opioid with a slow(ish) onset.

 

[adder]

Concerning retaining 1 MOR agonist / NMDA blocker on the market, well, methadone has such pharmacodynamics as well (of course it's different from levorphanol if one were to look at it totally). Methadone has 2 advantages over levorphanol that popped in my head right away after I had read your post. The first one is that it fills the hole on any market of an opioid with NMDA blocking properties being a good drug for substitution as well (levorphanol doesn't make a good substitute, IMHO it has a lot more dependence liability than methadone). The second one is when used as a painkiller its analgesic effects last similarly long in time to levorphanol (anyway, as a painkiller methadone is dosed 2-4 times a day, levorphanol wins this battle IMO but only by a margin so having a higher dependence liability levorphanol loses). I'm basing all of this on my own experience. I abused racemorphan and then levorphanol a lot during the last months before I switched to buprenorphine and eventually methadone. Although levorphanol is a smooth opioid, no rush after i.v., it's very euphoric and euphoria lasts for hours. Methadone alone can make me extremely sedated at most, it does more with clonazepam but I've been on clonazepam for quite a while and generally on benzodiazepines for 7 years so it just lets me survive. Methadone starts to be interesting as recreational drug if combined with some benzodiazepine and brompheniramine/chlorpheniramine/triprolidine/smoked Atropa belladonna leaves (from 1st generation antihistamines these gave me the best results). But still it's far from an euphoric opioid ride.

Concerning benzomorphans, I didn't write they were opioids with high dependence liability. I just mentioned phenazocine as being superior to other mentioned benzomorphans because there was a discussion over N-2-phenylethyl, N-2-(2-furyl)ethyl, and N-2-(2-thienyl)ethyl derivatives. They boost MOR affinity so phenazocine having a phenethyl on nitrogen gives less unwanted effects from kappa and sigma or it's rather more balanced. Nonetheless, it was still far from substituting any 4,5-epoxymorphinan derivative with MOR +++, KOR +, DOR + properties. Morphine is a good example of perfect balance in activating respective opioid receptors. No wonder it's a gold standard.

 

[Hammilton]

Many countries seem to retain 1 MOR+/NMDA- agent for medical use & levorphanol is supposed to be just about the best of this class but it appears that the addictive liability may be higher than some other opioids. The only reason for the N-phenylethyl was to reduce costs (this was very old research, Grewe synthesis-era).

It's not like this is done with some sort of plan in mind, they're not 'retaining' it they just aren't banning it.

 

[fencamfamine]

Adder: I realized that the ester would just produce a prodrug but thought that the phenol was the feature that slowed down BBB penetration? Desomorphine (Permonid) has the epoxy bridge and is noted for it's rapid onset. I have no idea if it has a rush, but it's certainly popular in certain regions of Russia ('The Crocodile').

Transport of this class of opioids is very interesting. I noted that in the book 'Opiates' by George R. Lenz et al, 14-substituted analogues are discussed & it was increased transport of the esters that increased potency (according to them). The only people who seem to have investigated morphinans with this additional functional group are Bristol-Myers (before Squibb acquisition). In all of the patents they are careful to avoid full agonists. The only commercial application seems to have been Stadol (butorphanol). The synthesis didn't look TOO friendly. Retrosynthesis may be the most practical route for small samples.

Of course, I have yet to investigate the details of ethers at the 14 position. A (m)ethoxy in combination with a 5-alkyl seems to produce very pure MOR agonism as well as DOR activity making them potent analgesics in animal models. I somehow doubt that these compounds will be adopted in Afghani farmers any time soon

 

[adder]

Yes, I heard about "the Crocodile". It's terrible how far people are ready to go to achieve desired effects. Opioids, sir! And yes, it's got quite a fast rush but to be honest some compounds much more potent on a weight basis than morphine lose this "magic" at some point. I mean, I've always praised morphine for its rush, for me it's superior to e.g. heroin because of more physical effects. Sometimes an inherent part of increasing potency is lowering recreational value. Potency, affinity, and internal activity are different things and that's just about it. But I guess people would go through this dirty synthesis from codeine even if it had no rush, it's like 10 times as potent as morphine so 100-120 as potent as codeine. What a gain if the synthesis is completed in lab conditions! Well, the problem with Russia is although they have brown heroin from Afghanistan and at very low prices when converted to dollars or euro for an average Russian it's very expensive. So addicts seek other ways of achieving opioid high. I've observed the similar situation in Ukraine, heroin in Kiev cost [snip] 2-3 years ago. This was actually equal to prices here in Poland (and here even now when the price of heroin increased drastically and quality decreased people keep taking it, well, methadone started being a little bit more popular on the black market but still). In Ukraine addicts are more into amphetamine or marihuana, they don't have money to buy heroin or cocaine (and both drugs travel through their harbors, just in different directions). Anyway, those stories from Russia about desomorphine and tianeptine are sad. I sympathize with those people, narcotic madness is capable of pushing people to irrational actions.

Concerning (-)-3-acetyl-N-methylmorphinan, well, the literature clearly states that acylation of morphinans at 3 doesn't alter intensity of analgesic effects but shortens duration of action.* To be honest it's a tough nut to crack for me to explain it but it's enough for me if it's been examined and the source is reliable. I've never actually done this and I haven't thought about it but I guess one would have to look at both levorphanol and its 3-acetyl analog from the perspective of physical chemistry and analyze charges on various atoms. Acylation has different impact on various classes of opioids.

There shouldn't be much difference between 3-acetyllevorphanol and levorphanol actually. No rush for sure in either case (I didn't notice it) and I doubt that this acetyl group really helps in getting molecules through BBB that much, it's probably just a tad subjectively. So yeah, the fact that it's on phenol is the simplest explanation and probably true.

Nonetheless, morphinans are an interesting class to play around with. With removing more and more rings, the situation changes with benzomorphans but they're also interesting because there are compounds with a wide spectrum of different agonists and antagonists (and dualists if someone recognizes them in this division).

* Synthetic Analgesics, Part IIA Morphinans, by J. Hellerbach, O. Schnider, H. Besendorf and B. Pellmont; Research Department of F. Hoffman - La Roche & Co. Ltd., Basle