Novel Opioids

[Feretile]

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The above viminol analogue is some x318 morphine BUT it was never trialled on man (although simpler analogues were and the estimation of activity was correct).

I cannot help but reflect that their is still room for increased potency. Terminal -CH3F possibly and the replacement of the aromatic all offer routes to increased activity. I should add that the syntheses and workup make it a compound of theoretically activity and no more. When the Chinese know of p-No2 azaprocine (OK, only x25 M) then it represents a 3 step compound which offers MANY different pathways.

 

[Feretile]

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[Feretile]

There are an almost unending number of patents concerning opioids - it's just a matter of data-mining. I keep adding so others can produce training sets.

 

[Fertile]

If you also consider BDPC and that propanamide class I noted, benzylamine opioids come in QUITE a few shapes. I note that, in essence, the tertiary amine and the ester/ketone long-pair are reversed - this suggests that they bind at a different site in the receptor cleft.

 

[Fertile]

US3093652​

Alkyl 1-(2-aryl-2-oxoalkyl)-4-phenylpiperidine-4-carboxylates and their preparation

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The above just shows that the beta ketone & betahydroxy derivatives of pethidine do follow QSAR.​

 

[Fertile]

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I found this via Reaxys and it's from a German article. It is on the Eunoia disc (for those that have it).

The ethylsulfonate & n-propylsulfonate homologues were both equipotent with ketobemidone.

I've always been fascinated by ketobemidone, especially when I discovered picenadol. What is interesting is that the (3R,4R) enantiomer of picenadol is a pure agonist while the (3S,4S) enantiomer is a pure antagonist. Now, I KNOW that researchers tried adding a 3-methyl to ketobemidone but it wasn't very active. Looking back, I do wonder if they separated the enantiomer. If not, they would end up with a mixed agonist/antagonist and so it would not have fitted in with the known (at the time) QSAR.

Well, 25mg of ketobemidone is supposed to be as potent as 60mg of morphine making it about 2½ more potent. IF it turns out to follow the prodine QSAR then then the most potent enantiomer of 'methylbemidone is very likely the (3R,4R). It's dangerous to simply multiply up potency values BUT (3R,4R) methylbemidone could be about x20 morphine.

If someone could quietly obtain the chiral precursor (say 1-[(3R,4R)-4-(3-hydroxyphenyl)-3-methylpiperidin-4-yl]propan-1-one) then it would be an interesting RC.

Sadly, since the UK introduced the CsA laws, it seems that RC vendors don't employ medicinal chemists. I haven't seen a single new scaffold in a decade or more.

Of course, U-47700 was almost a PERFECT RC because it could be made in bulk in 1 step from 2 commercially available chemicals.

I have been saving up U-93951 but nobody is prepared to invest in developing anything new (development takes time, resources, skills and most of all - MONEY).

*Edit*

I've found an English language patent for the ethanesulfonate analogue of ketobemidone: US 2777850 '4-ethanesulfonyl-4-aryl-1-methylpiperidines and their preparation'.

I am very suspicious of Sydney Archer who, if the patents are to be believed worked on a HUGE range of compounds. It seems more likely that the Germans didn't patent the class and with their being no English language versions of the paper, got away with patenting it. That or BASF sold all of their US rights to Sterling Drugs and Mr. Archer got his name on them all.

 

[Valentine4]

Not to rain on the parade, but I don't think my old high-school chemistry set will allow me to synthesize these... It saddens me this interesting topic may remain theoretical unless someone can reproduce these interesting compounds.

Anyone working on that? Then again, fentanyl synthesis has been all but mastered by darknet chemists, so I quite doubt they would spend time researching these interesting/forgotten opiate angonists.

EDIT: Sorry, Feretile literally just mentioned this dilemma in his last reply.

 

[Fertile]

Some are more accessible than others. There are literally millions of compounds that are commercially available and about as many more that are intermediates to a commercial product and can, wish some lengthy communications, obtain them.

I think it important to note that the dimethylaminopivalophenone most certainly hasn't had much work on elucidating the QSAR.

It's also worth noting that the mu and delta receptors are very similar so if you have a ligand for the latter, it may be possible to adjust it's structure to act on the former.

And of course, their is new stuff in the pipeline all the time.

 

[fastandbulbous]

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Bola V. Shetty in US Patent 4210749 'Substituted 1,2,4,5-tetrahydro-3H,3 benzazepines'.

It's interesting to see the piperizine moiety turning up again. Elements of phenapromide. The methoxy analogue is orally active and x2 pentazocine, the phenol (O-desmethyl) analogue was found to be x8 pentazocine but was not orally active.

Thing is, are compounds that have their activity stated as so many times pentazocine, the sort of thing to be considered viable areas of research into producing novel painkillers for medicinal use? The kappa receptor activity of pentazocine resulted in it being withdrawn from theraputic use (my ex, who was a vet. nurse, recounted the story of a Rottweiler that had to be brought back to the vets, for growling and aggressive behaviour towards non existent entities. My personal experience with it was that I stood up, turned around and became lost/disorientated in my own home). Seeing how shit scary full kappa agonist, like salvanorin A can be, I think most people would choose to remain in pain.

 

[fastandbulbous]

It's still LOADS more than I have,

BTW take a look at the opioid nortilidine and K. The 1 fact you lack is that the N: & (lone pairs) interact which is why nortilidine has NMDA properties. Oh, and in a patent I saw, m-MeO nortilidine was produced. So opioids & NMDA antagonists are CLOSE.

Oh, and like K, the isomer of nortilidine that is not an opioid is a DRI.......


Nortilidine comes as a pair of enantiomers (chral pair) so one is mu/NMDA & the other is DRI....... ok so it's only x2 M in potency BUT it's very euphoric.

Not the only drug where optical isomers have much different activity: racaemic MDA is a weird mixture, the S & R isomers being markedly different (there are others, but three weeks of morphine, for a septic abscess - courtesy of one of my kitties - has left me a bit feeble minded!)

 

[Fertile]

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I'm sure people recognise BDPC, but I found a paper on novel propanamide class. If you overlay aromatics, N: and O: you will discover that they overlay very well indeed.

EP 1 055 665 A1 covers this novel class. I am confident that it is active and modifications seen to increase BDPC activity will likewise see increase activity of the novel class.

Pity it's not so easy to make. BUT it's useful when building a training set.

 

[Fertile]

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Here is an unusual one. The people who developed it did not specify the activity of the isomers. Often new compounds undergo a standard test of tests and this turned out to be a pretty potent opioid. I presume it's because it's rigid compared to most synthetic opioids.

If 5-(3-methoxyphenyl)-2-azabicyclo[3.2.1]octane is used commercially (i.e. cheap_ then it might be an attractive target.

 

[izo]

If 5-(3-methoxyphenyl)-2-azabicyclo[3.2.1]octane is used commercially (i.e. cheap_ then it might be an attractive target.

ok, im not sure if the bridged methylen group is neccesary, sure increases potentcy, and the furan could be swapped by a plain phenyl, could increase potentcy. never saw a arylethyl group on an opioid N where a furan was used, too small to fit the pocket. thiophen or phenyl is better id say.

i had the furan analog of methcathinone. it has a vile taste and a very short duration, not big enough to stay long enough in the receptor. the pyridin analog of a-pvp has even less activity, almost none and tastes a little bit better than a-pvt. the only amphetamine analog with thiophene that you can actually vape. mpa had as disguisting taste and thiothione was distguistingly sweet.

 

[Fertile]

I should add that the 2-(2-furanyl)-ethyl was the most potent of a series. I didn't post them all. The bridge isn't required, look at things like meptazinol, but it will make the molecule more rigid which generally increases potency. Of course, meptazinol is a partial agonist. The compound I list is a full agonist

 

[izo]

Of course, meptazinol is a partial agonist. The compound I list is a full agonist

yea also thought about meptazinol.

 

[Fertile]

Well think about it - a 7 membered ring is not all that stable. It has several similarly low energy conformations (i.e. body heat is enough to cause interconvention).

 

[izo]

yea, 5 and 6 membered rings are favored...

 

[Fertile]

Well 5-membered rings also have multiple near-minimum energy conformations. I seem to recall profodol is a mixed agonist.
That is an interesting issue when it comes to phenolic opioids - will they be agonists/antagonists/mixed. As you know, it's the position of the N: that yields agonist/antaconist.... and so in the case of profodol, the N: is moving.

This detail about the N: was understood by producing quaternary salts of the amines & resolving isomers. While they cannot cross BBB due to formal charge, it's still possible to test in vitro.

 

[Fertile]

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Yes, and the furan is by far the most potent. See similarity to Ro4 1539

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[Fertile]

But here is the thing - I cannot find the N-2-(2-furanyl)-ethyl moiety in any morphinan with an epoxy bridge. Maybe it's just because the more complex (fully synthetic) compounds above were made a decade or more later than the semi-synthetic examples with the bridge.... or maybe the furanyl doesn't work if the bridge is present.