Overlay Fentanyl (x80 M), 4-phenyl Phenapromide (x60 M) & N-phenylethyl Dimethylaminopivalophenone (With a look at Diampromide)

[Feretile]

Fentanyl - Wikipedia

en.wikipedia.org

Phenampromide - Wikipedia

en.wikipedia.org

Diampromide - Wikipedia

en.wikipedia.org

Dimethylaminopivalophenone - Wikipedia

en.wikipedia.org

If you take the trouble to overlay all 3 of the above compounds, you will note that in each case, the 2 benzene rings & the basic nitrogen overlay PRECICELY. Now, IMO fentanyl & 4-phenylphenapromide are equipotent although Janssen claims x80 while the American Cyamid Company only claims x60 for 4-phenylphenapromide. For diampromide they only claim it to be equipotent with morphine.
So is diampromide so much less potent? The answer is simply that it's compound with a flexible structure and in which the lowest energy state does not conform to the mu opioid receptors.. Still, in example 11 of the patent, they do give the p-Nitro homologue as an example. In other cases (p-nitro azaprocin, nitreridine & p-Nitro analogue of metofoline), the p-Nitro increases potency by an average of around x10 so ir's possible to produce sufficient potency for a synthetically simple opioid.

Since Dimethylaminopivalophenone &Methyl,((p-nitro)-2-phenylethylamino dimethylaminopivalophenone EACH take 1 step (although I suspect a custom precursor would have to be produced for the second), such simple synthesis (read cheap) for a LEGAL product that I guess is going to be about x10 M seems like a good target. So I canvass opinion. Any more opioids baring the (p-nitro)phenylethyl moiety would be appreciated. Of course a -OH on the beta carbon of the PE moiety increases potency around x2 (x4 if chiral).

vcal hosted at ImgBB

Image vcal hosted in ImgBB

ibb.co

BTW actually, the p-Nitro is important because it increases the steric bulk. Without the -NO2 I would go for a 3-phenyl-3-hydroxypropyl moiety as seen in:

Phenoperidine - Wikipedia

en.wikipedia.org

 

[S.J.B.]

Dimethylaminopivalophenone - Wikipedia

en.wikipedia.org

Unfortunately the therapeutic index looks pretty bad.

I would also be careful with nitro groups in drugs that haven't gone through clinical trials, they are often associated with toxicity and tend to be avoided in modern drug discovery programs unless there's a good reason to keep it.

 

[Feretile]

Unfortunately the therapeutic index looks pretty bad.

I would also be careful with nitro groups in drugs that haven't gone through clinical trials, they are often associated with toxicity and tend to be avoided in modern drug discovery programs unless there's a good reason to keep it.

I have very closely considered the metabolic pathways for any compound I suggest. The nitro group is found in several other opioids that HAVE been through trials, specifically as p-nitro phenylethyl moieties. as I pointed out. In all cases the result is reduction (unusual since the body is generally an oxidative instrument) Aromatic amines most certainly can be mutagenic but only because they are on an aromatic with further substitutions and said heterocycles are mutagenic and/or affect hERG proliferation. N-dealkylation & hydroxylation of the dimethyl moieties are the other pathways. A small amount of p-hydroxylation of the benzene ring will also be expected.

Please don't think I'm not appreciative of people sounding notes of caution but I have quite a lot of experience in drug design. I am prepared to try things I design but if it looks good, it goes to Huntingdon Life Sciences for animal models. I was first into man so my wife is then first into woman, my son was first into son. That was my gauge, I would ask 'would I be happy for Ollie to take this' and I threw some away. Some that later turned out to be dangerous. Methoxyphenidine, for example.... the bk-2Cx series. The former was toxic, the latter could dimerize and the metabolic pathway could get too complex to work out.

Like all things, it's 1% inspiration, 99% inspiration. I didn't just come up with the compound today, it's something I have been considering for about 2 years. I wanted to collect all of the related patents & related compounds & then to finding ALL of the metabolic pathways.

Oh, I've just remembered that in example 11 of US Patent 3719669 (See Wiki aniliopam), they also disclose the p-Nitro-2-phenylethyl analogue. The reason the p-Nitro-2-phenylethyl analogues aren't seen much is because their duration is short (40 minutes or so) before they are reduced to the p-amino-2-phenylethyl which us generally about ¼ the potency of the nitro. As you can imagine, they do not find much medical application because their would be a 2-phase metabolism. You would not be able to keep giving the p-Nitro without the p-Amino accumulating (lasts 2-3 hours(.... so the p-aminos are more usually seen.

I have just realised that tapentadol is a mixed agonist antagonist and to make a FULL agonist, all you need is 1 extra methyl group thus:

Tahexadol hosted at ImgBB

Image Tahexadol hosted in ImgBB

ibb.co

Tahexadol anyone?

Oh, an anybody wondering why making the side-chain 1 carbon longer will produce a full agonist, look at the patents on (3R,4R) Picenadol.... or just convert them to 3D, calculate the minimum-energy state & overlay them. It's also worth considering JDTic. A phenolic opioid with an alkyl side-chain on the alpha carbon follows a simple rule. Methyl = antagonist, Ethyl = mixed agonist/antagonist Propyl = agonist.

The thing is, the patent on tapentadol NEVER mention an example of an N-propyl side-chain. It's like the butorphanol patents that only provide examples that are mixed agonist/antagonist or pure antagonists BUT luckily, a research team from the 1950s tried every possible N-substitution: https://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1958-01-01_4_page007.html

 

[negrogesic]

Never heard of phenampromide, it reminds me of bucinnazine (the basis for the now ubiquitous 2-methyl-ap237)

 

[Feretile]

Never heard of phenampromide, it reminds me of bucinnazine (the basis for the now ubiquitous 2-methyl-ap237)

Download ACD/Chemsketch - it's free. You can overlay 2 chemicals in 2D & 3D. Until you 'see' the 3D, you don't REALLY understand the shapes. One of the 2 natural skills I have is that I am able to look at any chemical structure in 2D and to SEE it in 3D. Rotating about 50cm in front of my eyes. It's nothing to do with being clever, working hard or being a great chemist.... it's just something a few people can do.

IF you are spending 7 years studying medicinal chemistry then this is a happy coincidence.

Mu receptors have 6 important moieties that bind

1)Benzene (or phenol) ring
2)Oxygen lone-pair O: in a specific relative position & rotation relative to benzene ring(i.e. ester/ketone/sulfonyl etc)
3)Nitrogen lone-pair N: at a specific relative position & rotation to the benzene ring
4)Aromatic system in specific position & rotation relative to benzene ring
5)alkene in specific relative position and rotation to benzene ring. Only occasionally seen but alkenes in allylprodine,, 14-cinnamyloxycodone & etorphine are all in exactly the same position
6)EWG on benzene ring(s) alter biosteric minimum and electron density e.g. -NO2 in etonitazene, p-Br/-CH3 in BDPC/MDPC or p-F in p-F OHMefentanyl.

In addition, side-chains can help chemical fir receptor better BUT they also make the structure more rigid. In the case of prodine, it's to improve affinity but in the case of methadone, it's to make the dimethylamine to benzene 3D distance/angle fixed. There are ALWAYS exceptions and their are always those things that we cannot yet explain.... so I just accept that sometimes pattern matching is the simpleest thing.

AP-237 is unusual one. Why not read the Wiki reference on the ring-substituted analogues that are more potent or even azaprocin that is x10 morphine and it's analogues that are x25 morphine. If anybody finds a cheap & easy way to make 3,8-diazabicyclo[3.2.1]octane.

https://doi.org/10.1021/jo01066a032

 

[negrogesic]

Well my knowledge about opioid SAR is very limited, what little i know is the so-called "morphine rule" which in fact i don't even remember, something like quaternary carbon attach to phenyl or similar ring, tertiary nitrogen and something else i can't remember, I'm no chemist. Though i do look at more 2D structures than your average person. In any event when i saw phenampromide, which i hadnt seen before, first thing that came to mind was, " huh that reminds me of bucinnazine/AP-237".



I thought the

 

[Feretile]

Well my knowledge about opioid SAR is very limited, what little i know is the so-called "morphine rule" which in fact i don't even remember, something like quaternary carbon attach to phenyl or similar ring, tertiary nitrogen and something else i can't remember, I'm no chemist. Though i do look at more 2D structures than your average person. In any event when i saw phenampromide, which i hadnt seen before, first thing that came to mind was, " huh that reminds me of bucinnazine/AP-237".



I thought the

https://www.molinspiration.com/cgi-bin/properties - free online LogP/MW/biosteric minimum/R05 violations/3D minimum-energy calculations

https://www.acdlabs.com/resources/freeware/chemsketch/index.php - free 2D/3D Chemsketch. Converts image<-->SMILES<--->IUPAC

Google drugfuture <name of drug> returns patent & references

https://www.scribd.com/doc/11293123...-ISBN-012443830X-0-12-443830-X-978-0124438309 - Scan of the most complete book on the QSAR of almost every opioid known upto 1986. A MUST HAVE

https://sci-hub.yncjkj.com/ - millions of documents on drugs

I am gutted to have lost my scanned version of 'Opioid Analgesics Chemistry and Receptors'. I don't have $300 spare to buy it for the 9 pages I want!

 

[negrogesic]

$300 won't be necessary :

https://scholar.google.com/scholar_url?url=https://www.thevespiary.org/rhodium/Rhodium/Vespiary/talk/files/3386-opioid_analgesics_casy_parfittaede.pdf&hl=en&sa=X&ei=lgYCYvjoNoK7yATri5XYCA&scisig=AAGBfm3ycOxuUFwQxQB8TO9sUt0BL4llZw&oi=scholarr

 

[Feretile]

$300 won't be necessary :

https://scholar.google.com/scholar_url?url=https://www.thevespiary.org/rhodium/Rhodium/Vespiary/talk/files/3386-opioid_analgesics_casy_parfittaede.pdf&hl=en&sa=X&ei=lgYCYvjoNoK7yATri5XYCA&scisig=AAGBfm3ycOxuUFwQxQB8TO9sUt0BL4llZw&oi=scholarr

WOW! MANY THANKS - I will name my next design after you.... although gesic is taken.... and the rest might be unacceptable yo some, even if they have NO IDEA where the name came from!

BTW it wasn't 9 pages, it was a little over 3 lines. Now I am hammering the patents to find who derived from it. when I can tell, I will, but your help is noted & if the stuff is legal in your locale, I will ensure you get some.

 

[Feretile]

I have updated & referenced Janssen's work on the phenaprimide class. A 4-hydroxy increases potency to x150 M.

Although adding a chiral 3-methyl on the piperidine has not been tested (AFAIK), the 3,3-dimethyl analogue was produced. x450 M.

So, phenapromide and fentanyl have almost the same QSAR/

Kind of surprised that these have not turned up. The patent makes REALLY heavy weather over producing 1 precursor. Things have changed since the 1960s, it's no longer a problem.

 

[obviously_not_carl]

What, where is an eschenmoser salt cheap or easy or anything to produce?
Again, pulling stuff out of thin air?

I made dimethylaminopivalophenone and its pyrrolidino analogue and I actually liked them for what they were - mild and moderately strong opioids.

 

[purplehaze147]

My guess would be a piperidine ring elicits higher potency than an amino group in the spot where the right most nitrogen is. It's more lipophilic.

 

[AlsoTapered]

What, where is an eschenmoser salt cheap or easy or anything to produce?
Again, pulling stuff out of thin air?

I made dimethylaminopivalophenone and its pyrrolidino analogue and I actually liked them for what they were - mild and moderately strong opioids.

The pyrrolidino analogue of dimethylaminopivalophenone?

Well, if you overly dimethylaminopivalophenone with prodine, you see that one methyl overlays the N-methyl of prodine, the other overlays the 3,N-dimethyl piperidine of the latter compound. I did check this very carefully using Chem3D.

Something like diampromide MAY be possible but you would need to test the docking calculations and their are more certain ways to significantly increase the potency of the compound. The very dimethyl moiety allows one to substitute one for an allyl as seen in allylprodine. Since it would only have two isomers and not the four enantiomers of that compound, the racemate is going to be considerably more potent.

Why does the allyl increase the potency? Because it has pi bonds and acts as a fragment of a second aromatic ring. If you look closely at example 13 of the U-47700 patent you can see that the researchers did try adding a second aromatic ring BUT in that case it pushed the LogP too high. Again, overlay U-47700 with prodine and note that the N-methyl of the amide overlays the 3-methyl of prodine... so what do you think happens if you try replacing said methyl with an allyl moiety? Well the result perfectly overlays allylprodine.

It's important to note that with Chem3D, you have to draw the molecule roughly in it's active conformation before running the minimum energy calculations and even then, some drugs do not bind in their minimum energy conformation. The human body provides enough energy (heat) for the molecule to enter a near-minimum energy state which is why docking calculations are so important.

It's generally opioids that contain ALL of the key moieties that are potent and those that bind in their minimum energy conformation that are super-potent.

Dimethylaminopivalophenone amazingly has four of the key moieties (at least 7 are known, 8 for antagonists) in it's tiny structure so increasing that to 5 is going to be interesting.

FYI α,α-dimethyl-α-allylacetophenone IS commercially available, can be produced simply and minimum-energy calculations show that yes, the allyl DOES overlay that of allylprodine. I don't believe that a Mannich reaction will add to a terminal alkene.