• N&PD Moderators: Skorpio | thegreenhand

Etonitazene again

Holy_cow

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In morphine abstinent addicts in withdrawal, 1 mg etonitazene orally replaces 60 mg morphine subcutaneously.
Fraser F.H. et al.
Addictiveness of new synthetic analgesics. Add 2, Min. 21st Meet., Comm. Drug Addiction and Narcotics, Natl. Res. Council, Natl. Acad. Sci., Washington, D.C:, 10-11 Jan 1959

Etonitazene potency is usually given as 1000 x morphine, but here it is only 60 x morphine (orally vs. subcutaneously). The Etonitazene derivative I mentioned recently for having a therapeutic inxed of 25'000 is 5 x more potent than etonitazene or 300 x more potent than morphine, with an ED orally of 0.2 mg.

I can only speculate that the route of administration (orally) brings down the potency of etonitazene from 1000 x to 60 x morphine.
 
Perhaps it's not as potent in humans as in mice/rats (where that 1000x probably comes from). I've seen that more than a couple of times with other opioids.
 
Etonitazene potency is usually given as 1000 x morphine, but here it is only 60 x morphine (orally vs. subcutaneously). The Etonitazene derivative I mentioned recently for having a therapeutic inxed of 25'000 is 5 x more potent than etonitazene or 300 x more potent than morphine, with an ED orally of 0.2 mg.


Cow, whats this eto deriv youve alluded to??

SWIMs tried to find other benzimidazoles, particularly etonitazene derivs, with increased potency verse eto but hasnt had any luck, probably because SWIM has no access to journal publications :(

Also, have you heard of etonitazene having DRI activity similar to cocaine? I recall reading that somewhere but cant remember where and aint sure if it was just misinformation or what.


If thats true, thats VERY interesting pharmacology for an opiate, but of course, so is an opioidergic benzimidazole in the first place. But damn, DRI activity built into an opiate? Let alone a very potent opiate? Thatd be one savagely addictive drug. Throw in an MAO-B and god have mercy on your soul.
 
^^^ Meperidine's a DRI. And then there's that other opioid that everyone in here gets into every now and then that's like a combined opioid-stimulant.
 
Yeah, Lefetamine and (maybe) fencamfamine (I suspect it's Alcohol-like opioid receptor stimulation, not direct agonism).

There are actually quite a few opioids that have measurable ability to inhibit DA reuptake.
 
etonitazene is not a DARI, its a DA releaser and as far as i can tell it not potent enough to exert any stimulant effect at the sub-milligram doses required for the opioid effect. if i remember correctly its the same potency releaser as MDMA, not significant until you reach Highsmith level doses (100mg+) or am i wrong?

also what do you all think of the statement that etonitazene is "the most addictive drug in the world" is there any evidence to support that?
 
hamhurricane said:
also what do you all think of the statement that etonitazene is "the most addictive drug in the world" is there any evidence to support that?

IMO: No, there isn't, or at least it wasn't mentioned here yet. - Murphy
 
"Intravenous self-administration of etonitazene alone and combined with cocaine in rhesus monkeys: comparison with heroin and antagonism by naltrexone and naloxonazine."

Psychopharmacology (Berlin, Germany) 2009, no pp. yet given

Abstract

Rationale: In humans, µ-opioid-cocaine combinations (speedballs) have been reported to heighten pleasurable effects and result in greater abuse potential compared to either drug individually. Emerging evidence in animals suggests that the ability of µ-opioids to enhance the reinforcing effects of cocaine might be independent of their µ-intrinsic efficacy even though µ-agonist efficacy appears to be a determinant in the reinforcing effects of µ-opioids themselves.
Objectives: This study examd. the relationship between agonist efficacy, self-administration, and the enhancement of cocaine self-administration using the high-efficacy µ-agonist etonitazene.
Materials and methods: Rhesus monkeys self-administered cocaine, heroin, etonitazene, and opioid-cocaine combinations under a progressive-ratio schedule of i.v. drug injection.
Results: Unlike cocaine and heroin, etonitazene did not maintain consistent self-administration at any dose tested (0.001-1.0 µg/kg/injection). However, combining etonitazene (0.1-1.0 µg/kg/injection) with cocaine (0.01 and 0.03 mg/kg/injection) enhanced cocaine self-administration, and this enhancement was attenuated by naltrexone. These effects are similar to those obtained by combining non-reinforcing doses of heroin and cocaine. Antagonism of etonitazene-cocaine and heroin-cocaine self-administration by naloxonazine was short lasting and was not maintained after 24 h (when naloxonazine's purported µ1 subtype antagonist effects are thought to predominate).
Conclusions: The results suggest that high µ-agonist efficacy does not guarantee consistent drug self-administration and that the ability of µ-agonists to enhance cocaine self-administration does not depend exclusively on reinforcing efficacy. Moreover, the results do not support a major role for µ1-receptor mechanisms in either etonitazene- or heroin-induced enhancement of cocaine self-administration.

I would read this abstract as if etonitazene is NOT the "most addictive drug in the world".

- Murphy
 
I am aware of the chiral amide in the methylene spacer. Increased potency is almost certainly due to NOP affinity. The N lone-pair (of the S isomer) overlays that of the N piperidine of MCOPPB. That may be a very useful thing. It seems that both NOP & DOP affinity increases the analgesic activity without giving the same euphoria. I wouldn't like to say that is a certainty, but as someone with severe chronic pain, an opioid that doesn't produce tolerance and then dependence would make my life a lot better. The stuff is a disaster area in cases of abuse. A lab in Russia & Germany were discovered and at least 2 US citizens made their own and harmed themselves.

Super-potent opioids with a short duration are ravaging the west. If 5mg of fentanyl costs as little as $2 then it shows that the low-cost-many-unit model seen in crack can be employed. I don't know how those 'cooks' sleep. If I harm myself that is one thing, knowing that you are harming many people is quite another. It is interesting that more and more medicinal chemists on this site are not openly discussing things. Too many people will let all of the theoretical work to be done for free so they just send the stuff for the Chinese to make.

In retrospect, there are a few citations I wouldn't have posted looking back. While medicinal chemists are still somewhat gungho about possible harm to others is no excuse for others to adopt that low moral baseline.
 
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An appropriate, natural dicarboxylic acid yields flat prismatic crystals of the (S) isomer. A 3:1 methanol:water extraction media provides clean CCS for X-ray spectroscopy. Hmmm... not well tolerated, not of value, best to avoid.
 
That would be tartaric acid, no? at least tartaric acid is the one most commonly employed for chiral resolution of dextro vs laevorotatory isomers. The naturally sourced tartaric acid being enantiomerically pure whilst I have read reports from others that synthetic tartaric acid advertised as one or other isomer in enantiomerically pure forms have, even from major chem suppliers not been so. The natural form is both cheaper, easier to obtain and as is usual with natural products, enantiomerically pure.

Out of interest, rather than having any current practical use for such, how does one, short of separation by boiling point and distillation, if they differ enough, resolve a mixture of a compound which is pure, and yet, is composed of a mixture of cis- and trans- isomers?
 
..a mixture of a compound which is pure, and yet, is composed of a mixture of cis- and trans- isomers?

If it is mixture, then it is not pure! right? .. try Chromatography .. In general cis and trans isomers have different physicochemical properties so they can be separated by physical/chemical means like chromatography if one does not want to use fractional crystallization/distillation..etc).. The latter 2 methods are easier tho...

re: etonitazene: I came across something peculiar about this compound. Although a highly potent mu opioid agonist, Rhesus Monkeys would not self-administer it (at pretty much any dose) unlike coacaine and hereoine .. but the combination with cocaine enhance self-administration of the latter which is blocked by opioid antagonist naltrexone.. any idea what's up with this molecule?? here is the paper:

Intravenous self-administration of etonitazene alone and combined with cocaine in rhesus monkeys: comparison with heroin and antagonism by naltrexone and naloxonazine .. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2682624/ ..
Rationale

In humans, mu opioid-cocaine combinations (speedballs) have been reported to heighten pleasurable effects and result in greater abuse potential compared to either drug individually. Emerging evidence in animals suggests that the ability of mu opioids to enhance the reinforcing effects of cocaine might be independent of their mu intrinsic efficacy even though mu agonist efficacy appears to be a determinant in the reinforcing effects of mu opioids themselves.

Objectives

This study examined the relationship between agonist efficacy, self-administration and the enhancement of cocaine self-administration using the high-efficacy mu agonist etonitazene.

Methods

Rhesus monkeys self-administered cocaine, heroin, etonitazene, and opioid-cocaine combinations under a progressive-ratio schedule of IV drug injection.

Results

Unlike cocaine and heroin, etonitazene did not maintain consistent self-administration at any dose tested (0.001 mcg - 1.0 mcg/kg/injection). However, combining etonitazene (0.1 mcg - 1.0 mcg/kg/inj) with cocaine (0.01 and 0.03 mg/kg/inj) enhanced cocaine self-administration, and this enhancement was attenuated by naltrexone. These effects are similar to those obtained by combining non-reinforcing doses of heroin and cocaine. Antagonism of etonitazene-cocaine and heroin-cocaine self-administration by naloxonazine was short-lasting and was not maintained after 24hrs (when naloxonazine's purported ?1 subtype antagonist effects are thought to predominate).


Conclusions

The results suggest that high mu agonist efficacy does not guarantee consistent drug self-administration and that the ability of mu agonists to enhance cocaine self-administration does not depend exclusively on reinforcing efficacy. Moreover, the results do not support a major role for ?1 receptor mechanisms in either etonitazene- or heroin induced enhancement of cocaine self-administration.
 
As Wiki points out - US Patent 2,944,062

I believe it is LESS abusable. NOP agonism seems to blunt mu euphoria.


I don't know what molecular drawing software Wiki use. I've always asked 5MeODMT to draw the stuff for me but he's really busy these days. If anyone can, renaming R to R1 & adding the possible substitution in the methylene spacer on the benzyl moiety with either -H or -CONH2 would be a big help for people learning the QSAR.
 
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