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Novel Opioids

This one the (+) enantiomer has an ED50 of 0.049mg/kg.
pubchem.ncbi.nlm.nih.gov

4-(Benzyloxy)-2-((dimethylamino)methyl)-1-(3-methoxyphenyl)cyclohexanol

4-(Benzyloxy)-2-((dimethylamino)methyl)-1-(3-methoxyphenyl)cyclohexanol | C23H31NO3 | CID 11068634 - structure, chemical names, physical and chemical properties, classification, patents, literature, biological activities, safety/hazards/toxicity information, supplier lists, and more.
pubchem.ncbi.nlm.nih.gov pubchem.ncbi.nlm.nih.gov
[413587-97-0]
Ivars Graudums, et al. US5801201 (1998 to Grunenthal GmbH).
 
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Based on the data garnered in the last post I am hypothesizing Fentramtanyl:

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Fentramtanyl hosted at ImgBB

Image Fentramtanyl hosted in ImgBB
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This is only a guess though since for Serbian chemist in Yugoslavia, I think the 3-substituted analog of carfentanil steric bulk was not tolerated at this position.


The piperidine SAR could also work on bromadol or some sort of hybrid mixture of ideas based on all of the above.
 
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izo said:
yeah, every time these orange bottles in us tv series. over here everything gets blistered. also another difference is that in the usa can send commercials about prescribtion medicines like prozac. over here this is forbidden.

tried brorphine on its own lately, was not that impressed. lame opoid, but thats what i hear from all anilinopiperidines. is a proper etonitazene derivate any better? on had metodesnitazene, one of the lamest opioids i had, full dose around 500mg.
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As a -zene-naive, mostly opioid-naive (well, O-DSMT (IR) full dose could be, say, 100 mg for me now; did oxycodone a number of times @ 10–20 mg, max, years ago), what RoA is implied in your “500 mg full dose”? Just took 95 mg (IN) to be safe. Had done 31 (IN), and when that did nothing, 32 (IR) before, but that left no lasting impression…
Is this an IV-only kinda thing? (Cause I don’t IV/IM, anything with needles.) Boofing (IR) absolutely, though. I have 800 mg of this metodesnitazene left. How would you suggest I ingest it?
 
I only recently found out about BU72.
220px-BU72beta_structure.png

Even though it is almost 30 years old, it is still a novel opioid with an exciting pharmacological profile.
 
#27 (150x Mor)
N-[1-methyl-2-(4-hydroxy-4-phenylpiperidino)ethyl]propionanilide
pubchem.ncbi.nlm.nih.gov

N-(2-(4-Hydroxy-4-phenyl-1-piperidinyl)-1-methylethyl)-N-phenylpropanamide oxalate

N-(2-(4-Hydroxy-4-phenyl-1-piperidinyl)-1-methylethyl)-N-phenylpropanamide oxalate | C23H30N2O2 | CID 120615 - structure, chemical names, physical and chemical properties, classification, patents, literature, biological activities, safety/hazards/toxicity information, supplier lists, and more.
pubchem.ncbi.nlm.nih.gov pubchem.ncbi.nlm.nih.gov
Fancher, O. E., Hayao, S., Strycker, W. G., Sancilio, L. F. (November 1964). "New Analgesic N-Substituted Carboxamides". Journal of Medicinal Chemistry. 7 (6): 721–725. doi:10.1021/jm00336a008.
 
Smyth2 said:
What about Eseroline for an opioid?

I'm pretty sure that's clear of any analog laws if one is able to obtain this?
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It's an unusual one, isn't it. I'm not sure I'm comfortable with a compound that is shown to cause neuronal death. BUT I whenever I think 'nobody would stoop to placing the end user at such a risk', I find someone has done it. I think I'm correct in saying that it's found in a certain African plant and so it's quite possible that someone will pop up offering the 'extract' while highlighting that it's totally natural.
 
secretMotel said:
The Google Drive link to the opiates sections of the Annual Reports in Medicinal Chemistry that @izo posted is no longer working. Do you still have a copy @Feretile, or did anyone else happen to save the PDFs too and is willing to share it here again?
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Hello,

I hope this link work now:



I also have a relatively large collection about opioid papers that I can share here:

 
izo said:
Hello,

I hope this link work now:



I also have a relatively large collection about opioid papers that I can share here:

Click to expand...


Unfortunately, for me at least, the links you provided do not appear to work. Almost everything before about 2014 can generally be found on Sci Hub, Library Genesis or similar projects. So in the past I have simply provided hotlinks which also solves the hosting problem, which is a bonus.
 

CA 2309439 details the synthesis.

What neither of the above mention is the fact that ALL of the compounds in the series are chiral. In fact, I would go as far as saying that this omission is conspicuous by it's absence. The authors are also very careful to describe the compounds as 'modulators'. Both facts suggest a conscious effort to avoid drawing attention to them.

Luckily there are other examples of opioids in which both the basic amine and A aromatic are connected to the same carbon atom and they all appear to share the same chiral activity.
 
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n hosted at ImgBB

Image n hosted in ImgBB
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From 'Opiates' by Lenz et al.,

Page 441, Compound 82.

A. Wilson and A. W. Pircio, Nature volume 206, pages1151–1152 (1965) (London) 206, 1151 (1965)
'Narcotic Analgesics: Possibility of Broadening the Structural Basis of Analgesics'


See also:

Journal of the American Chemical Society Volume 86/Issue 22

'Ring Openings of Substituted Cyclobutanes Induced by Grignard Reagents. I. Methyl 2-Dimethylamino-3,3-dimethylcyclobutanecarboxylate'
Leonard. Weintraub Armin. Wilson David L. Goldhamer Donald P. Hollis


Anyone else notice that the very first novel opioid in this thread (image provided) is surprisingly similar to the paper and patent I referenced in my previous post?

It does suggest that μ activity (agonist - Example 4a) may be enhanced with a benzylic ketone or, if this part of the structure binds in a similar manner to fentanyl, an (S) beta hydroxy moiety.

Sadly I have been unable to find any information of the activity of the two isomers. I know from personal communication with Dan Lednicer (now RIP) that once BDPC had been discovered, the team was so surprised at it's potency in animal models that they felt there was no benefit in further research. Even MDPC wasn't tested. I asked why and his answer was simple 'In all the excitement, we forgot'. This is the stuff you don't read in journals, folks!

In retrospect, the p-Me is a much better target in many ways. It provides a sacrificial moiety i.e. that p-Me is very likely to be the major metabolic pathway via oxidation. The few reports on BDPC appear to suggest that it's fine for the first four hours or so, then it becomes deeply unpleasant. My best guess on this is that N-demethylation is the major metabolic pathway and the monomethyl metabolite has significant kappa activity.

A Chinese team confirmed that the beta aromatic ring of BDPC could be swapped and the increased activity of C-8813 confirmed whatever their research was designed to show. As far as I know, nobody tried substituting the cyclohexanol ring or adding a beta ketone/hydroxyl moiety. Or, if they did, I cannot find and references to that work.
 
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Title
N-benzyl-N-{8 2-phenyl-2-(4-phenyl-1-piperidyl)ethyl{9 {0 propionamide para-chlorobenzene sulfonate (sic)

Abstract
N-benzyl-N-(2-phenyl-2-(4-phenyl-1-piperidyl)ethyl) propionamide p-chlorobenzenesulfonate has effectiveness comparable to methadone in suppressing narcotic withdrawal symptoms and in maintenance therapy of narcotic addicted laboratory mammals.\

The above is a bit of an odd on because the patent doesn't cite and it not cited by any other patents concerning novel opioids and as far as I have been able to ascertain, the inventor never published anything else concerning novel opioids.

As far as I can work out. the compounds code name is TR-2923.

As people can see, TR-2923 has some similarities to 4-phenyl phenapromide but doesn't easily overlay the latter compound that has been studied in more detail. In spite of the inference that the compound substitutes for heroin, I tacitly suggest that the compound MAY be more of a sedative than an opioid so while rats would choose to imbibe the drug, it's more in the manner of a comfort medication.

I say that because while the researcher used naloxone to precipitate withdrawal, it doesn't seem that administration of naloxone was used to confirm that TR-2923 IS an opioid. I should add that nalorphine and latterly naloxone are used to demonstrate the opiate activity of a drug and had been the standard test for over a decade. So failing to perform such an apparently simple test seems odd to me.
 
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Smyth2 said:
This reminds me of Ciprefadol but the synthesis steps there appeared differently.

I checked my database and found another related agent called RTI-5989-31 if you are interested in looking into this?
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Yes. if you follow the patent citations you will discover that the original patent I refer to which only covers the N-methyl and N-phenylethyl derivatives were then further studied including the phenolic (antagonist) examples.

It's interesting to note that many opioids with an N-methylcyclopropyl moiety are AGONISTS (or silent agonists or partial agonists) in the absence of the phenol or bioisostere thereof. The 3-phenyl-3-amino propanamies I highlighted being one example.

When I mention bioisosteres, take a look at the patent covering 8-CAC. The phenol moiety is swapped for a carboxamide which proved to be chiral (a surprise to me) BUT is an antagonist... or at least an inverse agonist or possibly a silent agonist. Vague I know, but nobody since Nathen B. Eddy has ever been given the task of finding and classifying ALL of the opiates.

Even my friend and tutor Dam Lednicer was only ever asked to find a 'cheaper alternative to codeine' as was the renowned researcher K.W. Bentley. The former produced BDPC, the latter etorphine (and some compounds actually significantly more potent).

NOBODY is systematically trying to identify the class which is why @fastandbulbous always refers to the QSAR as 'black magic' because we still do not have a set of rules. I ALMOST had a set of rules, then tianeptine turned up.

But if nothing else. tianeptine gives us some insight into the receptor domain. While RO5 is a great way to optimize opiates. it's worth noting that only recently someone identified an active transport for compounds with a significantly higher MW/
 
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I found the above interesting in that it seeks to refine the N-phenylethyl moiety found in many non-rigid high potency mu agonists.

The compounds are listed in PubChem with multiple patents most of which are entitled 'Alkyl derivatives of 1-oxa-4,9-diazaspiro undecane compounds having multimodal activity against pain' . This is just another example of how patents now avoid explicitly stating that the new class of compound discussed are in fact μ agonists.

It's somewhat counterintuitive to discover that the addition of a 2,6 difluoro moiety to the benzene ring increased activity several times. Sadly they don't deal with the addition of a chiral beta hydroxy, a more commonly encountered substitution known to significantly increase activity BUT it's interesting nonetheless.

Many years ago I read a paper in which various (substituted) β aromatic rings were tested with the fentanyl scaffold. I'm sure people are aware that swapping the benzene for a 2-thiophene ring increases activity as it does with BDPC & MDPC. But the researchers trialled an array of different 5-membered aromatic rings with one, two, three or even four of the carbon atoms replaced by other elements. Some examples people might be aware of are such as alfentanil BUT it was discovered that thiazole, oxazole and other such ring systems were still quite active.

But here is the thing. While (S)- β-hydroxy-2-furnaylethane has been experimentally found the most active of the morphinan class, I cannot find data on the fentanyl homologue with that substitution. More complex derivatives which feature a 3-methyl substitution of the furan or a 4-methoxymethyl moiety are both known, but not the simpler example. So inactive and/or simply an artifact of PubChem's database compilation?
 
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www.mdpi.com

A Journey through Diastereomeric Space: The Design, Synthesis, In Vitro and In Vivo Pharmacological Activity, and Molecular Modeling of Novel Potent Diastereomeric MOR Agonists and Antagonists

Four sets of diastereomeric C9-alkenyl 5-phenylmorphans, varying in the length of the C9-alkenyl chain, were designed to examine the effect of these spatially distinct ligands on opioid receptors. Functional activity was obtained by forskolin-induced cAMP accumulation assays and several...
www.mdpi.com www.mdpi.com

I have come across the above class of mu agonist before but never an explanation of the stereochemistry.

The fact that early opioid were developed in an age before chiral resolution was practical means that nobody tried testing the 4 enantiomers of 3-methyl ketobemidone, for example. Otto Eisleb isn't alive to ask. But in the case I mention, picenadol MAY be a clue to the fact that unlike the related non-phenolic compounds, a researcher isn't faced with one isomer being an agonist, another an antagonist thus the racemic compound would not demonstrate activity.
 
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