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  • N&PD Moderators: Skorpio

Novel Opioids

It's possible given the large number of opioids known, some may have 5HTa2 affinity. But if, for some odd reason someone sought symptomatic treatments of severe pain AND something like the classic hallucinogens, it's better NOT to have a fixed ratio of the two activities i.e. take two things so you get exactly the dose of each that you want.
 
It cannot be discounted, but it's of no utility.

If you create a compound capable of having the appropriate activity at two totally unrelated receptor types, it's almost inevitable that it will prove to be promiscuous i.e. it will also bind to other receptors. The antipsychotics are one example. It's not unusual for them to bind to fifteen or even twenty subtypes of different receptors.

The informal term for this is 'dirty'.

That is why Paul Ehrlich developed the 'magic bullet' concept. If your drug is selective, it means a patient requires less of it and in theory making it less toxic.

But very few things are THAT selective. There are so many biological processes and the list is continually expanding so that sometimes it's drug toxicity that makes us aware of a process. I believe the first class of HIV medicines were based on the insight that RNA uses uracil for encoding while DNA uses thymine. So medicines that contain uracil isosteres would result in corrupting the transcription of the virus. But as it turns out, the body DOES use uracil so those drugs have side-effects.

You cannot look at a specific receptor or a specific chemical in isolation. The body is a hugely complex system. Even in the last couple of decades whole classes of medicines have reached the market only to be quietly discontinued when an unexpected toxicity was discovered.

That is why μ agonists is an interesting class. When viewed in 2D it can appear that they consist of many totally unrelated compounds but once viewed in their (near) minimum conformations, they are all actually very similar. I know Sandoz actually began with a 4-hydroxy-N-phentylethyl moiety and were able to derive some quite potent (x50 M) ligands.
 
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It's taken me a little while to find an index paper for the obscure (but potent) class of opioid analgesics developed by Sandoz. Compound 47 is the most potent in animal models.

It should be noted that the authors actually state that analgesic activity is between x30-x200 morphine depending on the test employed. To me, that seems a HUGE range.

As to why the racemate is more potent than either enantiomer is just one more unanswered question. But note that at this stage, nobody had recognized that for a compound to demonstrate antagonist (or inverse agonist) activity, it HAS to have a phenol moiety or bioisostere thereof.

The fact it only ever reached preclinical trials MAY suggest unpredictability. Note the reference to the earlier U.S. Patent 4178377 upon which this paper is largely based.

Still,, this compound apparently has affinity to all four classes of opiate receptor ALTHOUGH I must add the caveat that the affinity studies were carried out in the Norwegian rat. Still, it's another class that can be used in a training set.

Anyone who has viewed all of the high affinity mu ligands will recognize that the paper earlier in this thread that describes and alpha and beta aromatic which is apparent in this case. Of course, the active conformation of this class is a little more difficult to find.
 
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Fertile said:
ibb.co

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ibb.co ibb.co

I found the active isomer and discovered that the other isomer had no opioid affinity and so the above is x900 morphine in potency and can be made in 3 steps as the 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (which seems like a rare precursor) is in fact used as a precursor to several medicines including Imap, the long-acting neuroleptic often given as a depot medication. Since only 3 manufacturers exists ensure that it is commercially avsailable.

But stronger analogues are known:

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The above is x1100 morphine.

Oh, and in both cases the duration is 8 hours. So 0.25mg TID would prevent a rattle.
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I found a related opioid for sale recently called Spirochlorphine.
 
Smyth2 said:
This one is called R 6890. [3222-88-6]
39967.png


www.caymanchem.com

R-6890 (CAS 3222-88-6)

An Analytical Reference Standard
www.caymanchem.com www.caymanchem.com

Stahl, Kenneth D., Willem Van Bever, Paul Janssen, and Eric J. Simon. “Receptor Affinity and Pharmacological Potency of a Series of Narcotic Analgesic, Anti-Diarrheal and Neuroleptic Drugs.” European Journal of Pharmacology 46, no. 3 (December 1977): 199–205. https://doi.org/10.1016/0014-2999(77)90334-X.
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Spirochlorphine
 
Smyth2 said:
Spirochlorphine
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I fount a much later paper thar specifically build a QSAR for the NOP affinity of the class.

Synthesis and structure–activity relationships of N-substituted spiropiperidines as nociceptin receptor ligands


In fact, there are some even more in-depth papers in which MOP affinity was also tested. What interested me was that the NH was added to and that it seemed that such substitutions appeared to affect QSAR in a similar manner to the 4 substitution of fentanyl derivatives.

While of interest, they don's appear to be a facile target.
 
US3238216A

There is quite a lot out there but while I find it interesting, it's clear that unless one has access to 1-Phenyl-1,3,8-triazaspiro[4.5]decan-4-one (CAS 1021-25-6). it's a LOT of work.

There are more facile targets. Hence brorphine, I assume.
 
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paranoid android said:
Ketobemidone is one that i would really like to try
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Ketogan is sold as a 1:5 mixture of ketobemidone and Spasmolytic A29.
pubmed.ncbi.nlm.nih.gov

Ketobemidone plus (RS)-3-dimethylamino-1,1-diphenylbut-1-ene (A29) is more potent at NMDA receptors than ketobemidone alone: evidence for A29 as a non-competitive NMDA receptor antagonist - PubMed

The opioid, ketobemidone, has previously been shown to be a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. In Denmark, ketobemidone is available in a formulation which contains ketobemidone and a spasmolytic compound, (RS)-3-dimethylamino-1,1-diphenylbut-1-ene, hydrochloride...
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
 
Smyth2 said:
Ketogan is sold as a 1:5 mixture of ketobemidone and Spasmolytic A29.
pubmed.ncbi.nlm.nih.gov

Ketobemidone plus (RS)-3-dimethylamino-1,1-diphenylbut-1-ene (A29) is more potent at NMDA receptors than ketobemidone alone: evidence for A29 as a non-competitive NMDA receptor antagonist - PubMed

The opioid, ketobemidone, has previously been shown to be a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. In Denmark, ketobemidone is available in a formulation which contains ketobemidone and a spasmolytic compound, (RS)-3-dimethylamino-1,1-diphenylbut-1-ene, hydrochloride...
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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It's related to Demerol isnt it? I actually quite liked Demerol before my tolerance to opiates got to high to enjoy it. My tolerance to opiates was to high for the 400mg dose of Demerol a day limit. I took higher then 400mg's of Demerol a few times and it was not pleasant
 
krkkhed said:
Same, but people insist on K-opioid agonists causing dysphoria. Ive heard keto is super great though, it's been on my list of stuff to try for years but never have gotten anywhere close to trying it.
One can dream...
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I didnt know it was a k agonist. I havent tried any k agonist's yet unless you include salvia that is lol. I would like to try something like talwin or Stadol even but i have never heard of either being scripted here. Or any k agonist really
 
3DQSAR said:
US3238216A

There is quite a lot out there but while I find it interesting, it's clear that unless one has access to 1-Phenyl-1,3,8-triazaspiro[4.5]decan-4-one (CAS 1021-25-6). it's a LOT of work.

There are more facile targets. Hence brorphine, I assume.
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Here's the synthesis: https://ibb.co/w7fm10w

The Strecker-like condensation between N-benzyl-4-piperidone [3612-20-2] (1), KCN and PhNH3+Cl- gives 4-anilino-1-benzylpiperidine-4-carbonitrile [968-86-5] (2). Acid catalyzed partial hydrolysis of the nitrile to the amide afforded 4-anilino-1-benzylpiperidine-4-carboxamide [1096-03-3] (3). Reaction with formamide serves to form the spiroimidazolidone ring giving 8-benzyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one [974-41-4] (4). Catalytic hydrogenation then removes the benzyl group (5).

[1] Goebel, Tim; Ulmer, Daniela; Projahn, Holger; Kloeckner, Jessica; Heller, Eberhard; Glaser, Melanie; Ponte-Sucre, Alicia; Specht, Sabine; Sarite, Salem Ramadan; Hoerauf, Achim; Kaiser, Annette; Hauber, Ilona; Hauber, Joachim; Holzgrabe, Ulrike (2008). "In Search of Novel Agents for Therapy of Tropical Diseases and Human Immunodeficiency Virus". Journal of Medicinal Chemistry. 51 (2): 238–250. doi:10.1021/jm070763y.
[2] Janssen Paul Adriaan Jan, US3155669, US3155670, US3161644 & US3238216 (1964, 1964, 1964 & 1966 all to Research Laboratorium C Janssen NV).
[3] W Scharpf, US3839342 (1974 to FMC Corp).

Why not test the benzyl group is already strong enough without needing to deprotect and replace with another sidechain?
 
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