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Embutramide and related cmpds

polymath said:
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).

225px-Tianeptine2DACS.svg.png
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Nortilidine is the active and is a secondary amine. Dezocine is a primary amine.

If I have learned 1 thing about the 'Morphine Rule' is that it is incorrect.

It's the N lone-pair that matters, not the N itself.

I suspect that tianepine is a prodrug with the long haptanoic carboxylic acid being removed to form the active. Of course, that provides a chiral centre and I have not checked whichenthiomer is (more) active.
 
The "morphine rule" is not a hard and fast rule, more like a rule of thumb. And tianeptine itself binds to mu opioid, doesn't need dealkylation. Strange drug.
 
sekio said:
The "morphine rule" is not a hard and fast rule, more like a rule of thumb. And tianeptine itself binds to mu opioid, doesn't need dealkylation. Strange drug.
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I was just being my pedantic self. :) No offence intended. It always bothers me when something throws all my education out of the window.

There are certainly 6and I believe 7 moieties that bind to the mu receptor. In one book, etorphine's moieties are listed as are the analogues where the N-pentyl is replaced by a 2-phenylethyl and it's something like:

-Aromatic A (a-ring)
-Phenol or bioisostere on a-ring.
-Quaternary Carbon
-Nitrogen lone-pair
-Interaction of oxygen lone-pairs of 6 -OCH3 & 18-OH (etorphine with 6 -OH3 removed is only x25 M)
-Aromatic B (c-ring)

But I say that an alkene is also an important binding site. Overlay allyl prodine & 14-cinnamyloxy codeinone.

The rigidity of the compound is also important.


Duel agents (agonists) are much more potent and much more euphoric

mu/delta
mu/NOP (ORL1)
mu/NMDA
mu/dopamine release

As you know, a simple mu/NMDA/dopamine releaser like trans nortilidine turned up in Germany just once (reported by 7 users on the Land der Träume website (German). All were experienced in tilidine users and they all placed trans-nortilidine it at the very top of their favourite drug lists. It has the molar potency of morphine but the synthetic pathway was so long (5 steps), complex & low-yielding & the precursors so expensive that it was not economical. I think they paid €60-€80 per gram and that was directly from a German RC maker.

Of course, all of the papers & patents are on the Eunoia Disc but that is all from the 60s & 70s. Since then I discovered a new (to me) reagent that was discovered in 2007 that can produce the trans material (so no separation/epimerization steps) and if I am right, it's just 2 steps using very common reagents.

Sad really because as things stand, lots of fentanyl analogues and a handful of other potent opioids are flooding the market. Dangerous stuff with a supply chain that doesn't care about the end users.
 
Lypophylic?
I think it might be due to the fact that maybe it's demethylated metabolite might be much stronger?
 
Gaffy said:
Lypophylic?
I think it might be due to the fact that maybe it's demethylated metabolite might be much stronger?
Click to expand...


I believe that the LogP of the nor compound is slightly less favourable than the parent compound. It's the position of the nitrogen lone-pair. Although quaternary amines cannot pass BBB because they carry a formal charge BUT researchers were able to confirm using morphine methyl bromide (if memory serves) that it's the N: not the N itself.

If you look at dezocine, you will note that it is a primary amine that is active.

My own key step is opening an N-methyl azididine to produce an amino-ester. I'm sure you can see where I mean. Of course, MAKING that azididine ring in 1 step is the more well researched step although the reagent isn't well known.
 
It's "aziridine" for the nitrogen heterocycle with 3 members, and can't you make them from a-haloamines? I recall aziridines being present in some methadone syntheses from 2-chloro-1-dimethylamino-propane.

Trans nortilidine and clubcard's mystery euphoriant are actually reasonably close cousins. Tilidine has always seemed quite interesting to me, shame it is not seen more widely.
 
sekio said:
It's "aziridine" for the nitrogen heterocycle with 3 members, and can't you make them from a-haloamines? I recall aziridines being present in some methadone syntheses from 2-chloro-1-dimethylamino-propane.

Trans nortilidine and clubcard's mystery euphoriant are actually reasonably close cousins. Tilidine has always seemed quite interesting to me, shame it is not seen more widely.
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Indeed you can but previously not in 1 step from alkene. The aziridine to the amino-ester also took 2 steps & a chiral resolution. Now it's just 1 more step i.e. a total of 2 steps (not including formation of addition salt).
 
Why look into something like this? It feels like Tom Riddle asking about Horcruxes :p
 
Lajtai, A., Mayer, M., Lakatos, Á., Porpáczy, Z., & Miseta, A. (2016). Embutramide, a Component of Tanax®(T-61) as a New Drug of Abuse? Journal of Forensic Sciences, 61(2), 573–575. doi:10.1111/1556-4029.13010

Typical isn't it. We can produce much safer, much better compounds for recreational use except that the law is happy for people to get drunk but not high.

As I noted, we can improve on almost EVERY scaffold (safer, more euphoric) but we will never be allowed to. OT I had a sample of the reversed ester of nortilidine made. I'm glad I gave almost all of it away or I would have been taking it every 4 hours in increasing doses!
 
Dear Sir, embutramide is from Hoechst. Although it is a powerful synthetic opioid narcotic used for euthenasia of animal, if you take the penultimate compound, instead of reacting with GBL you perform a reductive amination with P2P.

Now, instead its application is for heart disease. A so-called coronary-vasodilator. This patent is also a compound by Hoechst.
 
Gaffy said:
Why look into something like this? It feels like Tom Riddle asking about Horcruxes :p
Click to expand...
Who's Gellert Grindelwald in this case? Someone who knows Dumbledore had the right equipment buried with him? Dumbledore would be Shulgin.
 
I am both fascinated and frightened. I can totally understand why such a simple chemical is active BUT the Chinese were happy to supply the trans-O-dimethylmethyl cyclohexamine. That's 1 step from U-47700.

I learned that 1 step is great, 2 steps maybe, 3 or more - too much work.
 
polymath said:
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 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 swisstargetprediction.ch
start.png


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

SwissTargetPrediction

swisstargetprediction.ch swisstargetprediction.ch
start.png
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soo what does this mean?
 
Loperamide is beyond RO5 (LogP) and I seem to recall that the little that crosses the BBB is actively removed (ABC?). Given that it isn't centrally active, does 5HT binding actually occur?

That said, US Patent 3714159 Table 1 suggests that even if the LogP is lower, it still does not accumulate.

On a related note, I recall that opioid dependent people were using handfuls of loperamide to reduce abstinence syndrome and for some, it did not end well. I don't know if the mechanism of toxicity was ever worked out but these people were taking hundreds of 2mg capsules at a time. Some ended up dead, some ended up in ICU with seriously bizarre problems such as compartment syndrome. Make of that what you will.
 
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