Embutramide and related cmpds

[sekio]

Embutramide is a potent opioid of novel structure used as a veterinary euthanasia agent (in combination with a few other drugs, brand name Tanax, T61 etc), it was apparently trialed as a human anesthetic but it has a very narrow therapeutic window, according to wiki the lethal dose is only 50% more than the effective sedative dose. The DEA apparently has this as Sch 3, and Clarke's lists several cases of humans commiting suicide with the commercial mixture sold as a euthanasia agent.

1. Are there any records of humans using this recreationally?
2. Are there analogues with better toxicity parameters?
3. Why is embutramide so toxic? Is it just a very potent dose/response curve like fentanyl?

 

[negrogesic]

Interesting, never heard of it.

Perhaps its much more likely to induce ventricular fibrillation than other opioids. It might have pronounced QT prolongation properties (more so than methadone or even loperamide) that results in rapid death.

 

[polymath]

The arrhythmic mechanism of dextropropoxyphene, methadone and loperamide seems to be blockage of cardiac Nav1.5 sodium channels.

Proarrhythmic mechanisms of the common anti-diarrheal medication loperamide: revelations from the opioid abuse epidemic - PubMed

Loperamide is a μ-opioid receptor agonist commonly used to treat diarrhea and often available as an over-the-counter medication. Recently, numerous reports of QRS widening accompanied by dramatic QT interval prolongation, torsades de pointe arrhythmia, and death have been reported in opioid...

www.ncbi.nlm.nih.gov

 

[Nagelfar]

200mg of loperamide a day for a good three years, only trouble if I went over 400mg a day or 700mg for a short stint of 72hrs, then stumbled, couldn't walk at a gram and quarter in 48hrs, only then hospitalized, idiot? yes: never do this. But maintenenced on it fine, that's not an endorsement, I think I may have had heart trouble when I couldn't walk, idiot; you get the picture(?)

 

[sekio]

My buddy was taking dumb amounts of loperamide and all it did was make him piss black, from overexcretion of the blue/green dye in the gelcaps he'd eat by the hundred.

 

[polymath]

When I had a few loperamide binges (about 96 mg a day) five years ago, it gave me a buzz similar to but less euphoric than codeine or morphine, and disgusting after-effects similar to alcohol hangover that lasted for 48 hours. Mostly an unpleasant experience, and with the possible cardiac complications, not a thing that anyone should ever do. A 16 milligram dose can boost a morphine high substantially if you don't have much opiate tolerance, and probably isn't enough to cause a risk of arrhythmias.

Edit: never tried to bite a loperamide pill, but that would be an easy way to check whether it is a local anesthetic (as you could expect from its cardiac side-effects).

 

[negrogesic]

From my experience i noticed no local anesthetic properties. Both toxicities stem from disruptions of cardiac ion channels, but i believe cocaine's cardiotoxicity is more sodium mediated where loperamide stems from being a pretty potent and long-lasting hERG inhibitor (potassium). Local anesthetics work via sodium ion channels but cardiotoxins arent necessarily sodium channel blockers, so they may be devoid of local anesthetic properties.

Ive had 96mg+ of loperamide as well. It felt a bit like meperidine, but dirtier.

 

[Nagelfar]

My buddy was taking dumb amounts of loperamide and all it did was make him piss black, from overexcretion of the blue/green dye in the gelcaps he'd eat by the hundred.

Never eat the gelcaps, how'd he handle the stomache burn? I mean, I'd do it when none other could be found, and I wanted to die before I got high, never changed my urine, and I've taken enough to have to be Narcan'd five times in hospital to keep me awake(!)

 

[negrogesic]

Never eat the gelcaps, how'd he handle the stomache burn? I mean, I'd do it when none other could be found, and I wanted to die before I got high, never changed my urine, and I've taken enough to have to be Narcan'd five times in hospital to keep me awake(!)

What was the highest dose you've taken?

How would describe how it felt?

 

[Nagelfar]

What was the highest dose you've taken?

How would describe how it felt?

Read above in this page: 1,250mg in 48 hours (four seventy eight count boxes in a day and following day 4 ninety six ct. boxes) I collapsed in a parking lot in which an ambulance was posted in about an hour after last dose, I couldn't walk, body kept wanting to bend over and fall. If emergency vehicle hadn't been insight I may've not made it through day, hospital released me with heart attack info, doctor who ok'd my release and nurse who saw me out both insisted it was slowed, funny heart rate, not a heart attack. Friend who picked me up insisted nurse took him aside to tell him I had indeed had a heart attack. That would have been nice to know if true, I might not have railed a forty bag of n-methyl amp crystals on way out in bathroom.

 

[polymath]

The Swiss target prediction seems to know for certain that loperamide binds to 5-HT2B receptor, and lists HERG as a possible binding site on the second page of the list.

SwissTargetPrediction

swisstargetprediction.ch

If the chlorine subtituent is replaced with iodine, the 5-HT2B is still the most likely binding site, but HERG is seen nowhere on the 7-page list:

SwissTargetPrediction

swisstargetprediction.ch

Methoxylating the tertiary alcohol drops the 5-HT2B down to 14th place on the list of likely binding sites:

SwissTargetPrediction

swisstargetprediction.ch

 

[S.J.B.]

The Swiss target prediction seems to know for certain that loperamide binds to 5-HT2B receptor, and lists HERG as a possible binding site on the second page of the list.

Let's be clear here: Swiss Target Prediction can give rough educated guesses as to whether a compound binds to a given receptor, with the guesses becoming more and more wild the more distant a structure is from known compounds with known binding to receptors/enzymes. However, in this case it states that there is 100% probability of binding not based on its algorithm, but because the database it uses to do these calculations includes assay data that shows that loperamide binds to 5-HT2B.

 

[polymath]

Yeah the most important thing about this is that loperamide could cause heart valve disease because it binds to 5-HT2B.

 

[clubcard]

The Swiss target prediction seems to know for certain that loperamide binds to 5-HT2B receptor, and lists HERG as a possible binding site on the second page of the list.

SwissTargetPrediction

swisstargetprediction.ch

If the chlorine subtituent is replaced with iodine, the 5-HT2B is still the most likely binding site, but HERG is seen nowhere on the 7-page list:

SwissTargetPrediction

swisstargetprediction.ch

Methoxylating the tertiary alcohol drops the 5-HT2B down to 14th place on the list of likely binding sites:

SwissTargetPrediction

swisstargetprediction.ch

Sadly, the dimethylamide moiety is not very active as an opioid (in fact, only the pyrrolidine has reasonable analgesic figures). The p-Cl also reduces central activity by an order of magnitude. The original patent lists dose & analgesic dose as a multiple of antidiarrheal dose US 3714159 column 8. Loperamide has a value of 640. Removing the -Cl has a much bigger effect. 4 lines down from loparamide in the patent is the compound without the -Cl & it is x25 more potent as an analgesic, 66x more potent as an antidiarrheal but the ratio is still 300.

Loperamide and related compounds are substrates for the ABC binding cassette so your body actively removes them from the brain. High doses of loperamide have lead to deaths and serious injury that has left people in hospital for months.

I THINK I came across Embutramide many years ago but it does look awfully hazardous. It's at the opposite end to the stuff I look at and consider. I mean, I've seen serious harm from loperamide but this stuff looks deadly.

 

[sekio]

I'm by no means suggesting anyone ingest a drug that is specifically listed as a compound to induce death rapidly (and painlessly I would hope) - doubly so as the mixture of multiple drugs it is sold as - but I was more interested in its unique structure. It's curious to note that it's definitionally a GABA-analogue (4-hydroxybutanoate group) and its relative simplicity, in fact it's very close to the minimum needed to adhere to the morphine rule.

Loperamide is garbage and I don't want the thread to diverge too far into talking about it, let's keep this on topic?

 

[polymath]

Loperamide is garbage and I don't want the thread to diverge too far into talking about it, let's keep this on topic?

Actually, there's one thing that I think would be useful to mention about it - loperamide is recognized as a known serotonin transporter ligand by the Swiss Target Prediction:

SwissTargetPrediction

swisstargetprediction.ch

I can't find the article where this is from, or what level of binding affinity it is, but this if probably a reason to not use or especially abuse it when on MAOIs.

 

[Nagelfar]

Loperamide is garbage and I don't want the thread to diverge too far into talking about it, let's keep this on topic?

So are used syringes, but I've used them to get high.

 

[negrogesic]

As a

I'm by no means suggesting anyone ingest a drug that is specifically listed as a compound to induce death rapidly (and painlessly I would hope) - doubly so as the mixture of multiple drugs it is sold as - but I was more interested in its unique structure. It's curious to note that it's definitionally a GABA-analogue (4-hydroxybutanoate group) and its relative simplicity, in fact it's very close to the minimum needed to adhere to the morphine rule

Are you aware of any MOR agonists or partial agonists that don't adhere, out of curiosity?

 

[negrogesic]

FYI i think the rule was something like

- a quaternary carbon atom
- a tertiary amine seperated from that quaternary carbon
- aromatic ring <---> quaternary carbon
- phenolic hydroxyl group situated meta to the quaternary carbon

 

[polymath]

Tianeptine has only a secondary amine (the other nitrogen is a sulfonamide nitrogen), and no quaternary carbon. There are probably many more, one that I thought about was a 3-methylcarfentanil with N-phenethyl group removed (maybe the other affinity increasing features in that one make up for the lack of tertiary amine).