Pharmacology Design a novel opioid - ask me how!

[4DQSAR]

Oh, sorry. Yeah - it was a group is Sofia who undertook to test ring-broken analogues of opioids.

They also highlighted the fact that 3,3-dimethyl fentanyl is stronger than raecemic 3-methyl fentanyl which I presume would make it a more appropriate target.

In fact, I have already snail-mailed that team and asked for appropriate articles. So old is the work, one of them died since so I've banged out letters to the rest.

 

[Smyth2]

I seem to recall it was a Serbian team of chemists who first made seco-fentanyl. However, only one article was ever made on that subject, although they made lots of fentanyl related articles at the time.

Given that the beta-hydroxy and alpha-methyl are both proven to enhance activity, I could not help but wonder how ephedrine would fare as one of the precursors. Phenmetrazine could also work.

Phenmetrazine is also used in the synthesis of Fenbutrazate & Morazone.

You have to admit it looks quite neat but nobody has access to phenmetrazine.

 

[4DQSAR]

Well it's the magic 15 carbon equivalents from tip-to-tip and certainly overlays things like phenapropmide and diampromide (bet the latter is more potent with a para substitution on the B-aromatic.

If memory serves, that chiral side-chain isn't like the one on 3,3-dimethyl fentanyl. If you replace with a dimethyl, it's inactive. The same team tested it out.

 

[4DQSAR]

BTW - you are quite right - the team is in Belgrade. Well, the surviving members are.

The pain is that Journal of the Serbian Chemical Socierty articles don't appear to have been digitized. I mean, not even as scanned images.

But I feel that knowing 3,3-dimethyl fentanyl (like 3,3-dimethyl prodine) will demonstrate the activity of the more potent enantiomer of the monosubstituted parent.

I BELIEVE someone unexpected like BOC patented 3,3-disubstituted fentanyl derivatives in the early to mid 70s. But I only glanced at the patent. Fentanyl strikes me as something best avoided.

 

[Smyth2]

I've not heard of 3,3-dimethylfentanyl before but I came accross a compound called 3,5-dimethylfentanyl, which was said to be a most promising compound:

Fentanyl-related compounds and derivatives: current status and future prospects for pharmaceutical applications - PMC

Fentanyl and its analogs have been mainstays for the treatment of severe to moderate pain for many years. In this review, we outline the structural and corresponding synthetic strategies that have been used to understand the structure–biological ...

pmc.ncbi.nlm.nih.gov

It's compound #30 in the above article.

I found 3,3-dimethylprodine has links on the pubchem website: https://pubchem.ncbi.nlm.nih.gov/compound/21120815

 

[4DQSAR]

AFAIK was only covered by a couple of the Journal of the Serbian Chemical Socierty articles. They were more generally trying to establish the size and shape of the lipophilic pocket that both that prodine and it's fentanyl counterpart took advantage of.

The article posits that for phenolic compounds, there isn't much difference in addinity between the enantiomers, but a difference in effacacy. BUT that isn't to say the same holds true for non-phenolic examples.

To me, THAT was the important detail. Although ketobemidone LOOKS so similar to prodines and so on, people presume they all bind in the same domain - which may well not be the case.

To further complicate things, Lednicer produced phenolic examples of BPDC homologues that were robust antagonists... which further muddies the waters.

 

[Smyth2]

Found it now: https://doiserbia.nb.rs/img/doi/0352-5139/2007/0352-51390707643D.pdf

However the potency was not determined making it appear as though it might not be that notable.

I found a completely ridiculous fentanyl analog here: https://www.caymanchem.com/product/28974/

You basically take the PEA sidechain and start making analogs e.g. 2cb

N-(1-(4-Bromo-2,5-dimethoxyphenethyl)piperidin-4-yl)-N-phenylpropionamide

N-(1-(4-Bromo-2,5-dimethoxyphenethyl)piperidin-4-yl)-N-phenylpropionamide | C24H31BrN2O3 | CID 165361468 - 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

 

[4DQSAR]

Some mania went around asing for the 2,5-dimethoxy-4-bromo derivatives of just about every class of psychoactive you can think of.

Someone with 10/10 money, 0/10 understanding.

 

[Smyth2]

Triadol (Tranydol, Tricyprodol):

I told 3DQSAR already about this in private but didn't want to leak it to the general public.

 

[Smyth2]

Camedol is another idea I have had for a long time but kept the idea in private and not leaked it to the general public.

 

[Smyth2]

This is a simplified version of bromadol that works on a piperidine instead of cyclohexanol.

For a similar patent see: US3311624.

 

[Rectify]

SAN_ANDREAS
1-(1R)-dimethylamino-2-(2R)-(1-(3,4-methylenedioxyphenyl)-1-oxo-2-oxaethyl)cyclohexane