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Pharmacology Design a novel opioid - ask me how!

This thread contains discussion about a Pharmacology-related topic
AlsoTapered

AlsoTapered

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Library Genesis

libgen.rocks libgen.rocks

Note Fig 1a.

That shows the 3D spatial relationship of MOST of the key moieties of MOR ligands. I might add 'not all' but I would like to take you along with me so if you could read that up so we are all on the same page. But you really need to think in 3D. Buy some of those plastic ball-and-stick models. The guy who discovered BDPC used just such methods (Dreiding models)
.
Then I will post the OTHER paper - yep, only two papers in this series.

Step 3 is we see what you all find - and voila, you get to name it/them.

please keep the discussion theoretical and avoid practical synthesis discussion. -skorpio
 
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When I enter the web page It shows a screen saying "file not found"
 
N-(2-dimethylaminocyclohexyl)-3-carbomethoxypiperidine.png


BETELGEUSE
N-(2-dimethylaminocyclohexyl)-3-carbomethoxypiperidine
 
Please don't post random molecules here - the mods were kind enough to give you your own thread so you wouldn't be filling up threads on specific topic.
 
Well half the links yoy provide are to antipsuchotics.

It's not a secret that Janssen discovered a relationship between certain antipsychotics and certain opioids, but the 6-fluoro-1,2-benzoxazole moiety is more associated with the antipsychotic end of things.

Unless you have at least some animal studies, it's rather hard to say how any compound will act in vivo. After all, in vitro models may provide affinity amd EC50 data which then may turn out not to be a good prediction when tested within a biological system.
 
Maybe provide the sidechain of spirochlorphine with R-56109.

This would be a separate analog though and not "Rispentanyl".

Brorphine is based on

4-(1-Benzimidazolinone)piperidine [20662-53-7]

Der List:
Benperidol, Zaldaride, Neflumozide, Pimozide, Bezitramide, Oxiperomide, TBPB [634616-95-8], Akti-1/2, FIPI, Flunamine type “hybrid” structure, R-28935, Brorphine, J-113,397, Trap-101, GSK1702934A, Jap DOR agonst i.e. PC22671431, R 4836, KF 4307, KF-4942, Tsuda (q.v.)., NS 521, ML272, N-benzyl group is morphine like analgesia, Bound to phenothiazine (US3873534), Peter Moldt (Neurotrophic phenethyl):

Ex 5: Peter Moldt, et al. WO1997040035 (1997 to Neurosearch A/S) .
胡春, et al. CN107652265 (2018 to Shenyang Pharmaceutical University).
Yoshinao Tsuda, et al. US4076821 (1978 to Welfide Corp).
 
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When you research the list you mention, you will note how closely research on antipsychorics throws up opioids. Brorphine was a Chinese team who took inspiration from Janssen's work in the 1960s in which he discovered several closely related compounds that were also analgesics.

Of course, the NOP receptor hadn't been identified and so I wonder if the analgesia was MOR and or NOP mediated.

There are a couple of patents from the last decade that exensively tested the 1,3,8-triazaspiro[4.5]decan-4-one scaffold. It turned out that the class has signficantly higher NOP affinity as compared to MOP affinity.

It's not as if 1,3,8-triazaspiro[4.5]decan-4-one isn't commercially available and a couple of years ago a fellow chemist asked me for the original references for 1-phenyl-8-(1-phenylethyl)-1,3,8-triazaspiro[4.5]decan-4-one which is commonly listed as posessing analgesic activity some x500 M. BUT what I DID point out that the compound is chiral and it's only in the later patent in which the enantiomers are resolved. I'm sure it comes as no surprise to discover that one enantiomer has extremely high NOP affinity, the other moderate MOP affinity. It was resolved and tested and I was told that it wasn't 'too good' i.e. it wasn't euphoric.

The same patent also covers examples in which the methyl of the amide is substituted with various moieties that approximated those encountered at the 4-position of the various potent fentanyl derivatives. They increased NOP affinity by orders of magnitude but didn't increase MOP affinity. I mean alkyls, alkoxys and methyl esters. If memory serves around 300 compounds were studied so that scaffold IS well explored and at least the prototype 'opiate' discovered by Janssen has been tasted and wasn't great.

Even that paper on 3DQSAR which I posted that used it as part of the training set failed to differentiate MOP and NOP.

Bioorg Med Chem Lett . 2007 Apr 15;17(8):2281-4.
doi: 10.1016/j.bmcl.2007.01.069. Epub 2007 Jan 27.
Synthesis and structure-activity relationships of N-substituted spiropiperidines as nociceptin receptor ligands
 
pubmed.ncbi.nlm.nih.gov

Novel Synthesis and Pharmacological Characterization of NOP Receptor Agonist 8-[(1S,3aS)-2,3,3a,4,5,6-Hexahydro-1H-phenalen-1-yl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (Ro 64-6198) - PubMed

The nociceptin/orphanin FQ opioid peptide (NOP) receptor is a widely expressed GPCR involved in the modulation of pain, anxiety, and motor behaviors. Dissecting the functional properties of this receptor is limited by the lack of systemically active ligands that are brain permeant. The small...
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov

I spent a while trying to find that paper but the above has a few relavent references. Note that the term ORL-1 is used. So clearly before the receptor was officially reffered to as NOP.

All I can say is the one member of the class that was tested in man proved not to be some sort of super-opioid.
 
Seems like they are all superstructures of tramadol. Maybe that's where the latter got it's name?

I guess I would consider synthesis - because steroid chemistry can be no fun at all. Dan wrote an entire book on it - possibly with best dedication in the history of publishing.
 
They are made from mestanolone, stanolone, & DHEA. These are only theoretical tramadol analogs and don't exist.
 
Well their is no absolute conformation information so I can't tell by looking if they would overlay tramadol. But whatever the case, seems a lot of work.

Experience has taught that 3 high-yielding steps is about as far as one can usefully go. Use convergant synthesis so that there are more than 3 reactions, but laid out sequentially, 3 is about it. Yes, for high potency stuff 4, but honestly, it was a BIG step up to 4.

Obviously pyrazolam was just bromazolam ---> thiobromazolam --> pyrazolam. Just two steps. But both are kind of tricky.
 
Hoe about Methamfentanil?

Basically you just do the Mannich reaction between methamphetamine, polyformaldehyde and acetone. Then reduce the Schiff-base with aniline and acylate.

There is also a bunch of analogs to consider. For example using ephedrine or phenmetrazine as the amine, and also considering acetophenone as the carbonyl.
 
This is the synthesis of stenbolone acetate that shows a Mannich reaction similar to tramadol.

I copied this method from Dan Lednicer's steroid book but I think the original reference is here:
Counsell, R. E.; Klimstra, P. D.; Colton, F. B. (1962). "Anabolic Agents. Derivatives of 5α-Androst-1-ene". The Journal of Organic Chemistry. 27 (1): 248–253. doi:10.1021/jo01048a060.
 
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Smyth2 said:
Hoe about Methamfentanil?

Basically you just do the Mannich reaction between methamphetamine, polyformaldehyde and acetone. Then reduce the Schiff-base with aniline and acylate.

There is also a bunch of analogs to consider. For example using ephedrine or phenmetrazine as the amine, and also considering acetophenone as the carbonyl.
Click to expand...

Isn't that aMF?
 
It's a dashed line to show it is a seco-analog. Note that seco-fentanyl in the original paper they did was not via Mannich reaction.

I was thinking maybe there is a stronger analog that can be prepared.
 
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