Ketobemidone derivatives. Are their agonist enantiomers and antagonist enantiomers?

[Fertile]

A few years ago I looked into ketobemidone derivatives. I found NONE. I was somewhat surprised but I noticed 2 things. Firstly, none of the studies resolved the stereoisomers and we know from other opioids which display mixed agonist/antagonist properties BECAUSE the product is a mixture of 2 isomers - Viminal (Dividol) being a prime example.

Then I discovered a compound closely related to ketobemidone, namely picenadol (LY-97435). The (3R,4R) isomer is an agonist while the (3S,4S) isomer is an antagonist.

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It seems likely that the reason is that ketobemidone was developed by Otto Eisleb at Winthrop Chemical Corporation in 1938 when stereoisomerism of new drugs went unexplored.

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Eisleb tried various different N-substitution patterns (more than a dozen) and whatever he did, the result was an antagonist. Pages 332-333 of 'Opiates' (Lenzm Evans, Walters & Hopfinger) details the many substitutions that were tested and while the N-methyl has agonist activity, while more potent analgesics were found, they conferred mixed activity.

But by 1975, Dennis M. Zimmerman at Eli Lilly revisited the ketobemidone scaffold and using newly discovered information, the 4 ethyl ketone was replaced by a simple N-propyl at the 4 position and a 3-methyl was introduced. Stereoisomerism WAS tested and it was found that while one isomer was an agonist, the other was an antagonist so even if Eisleb had introduced such a 3-methyl, the product would show no effect when tested on animal models.

But what is of most interest is that IF the agonist stereoisomer IS a pure agonist, will N-substituents normally associated with potent agonist activity be compatible. Eisleb tried these substitutions - substitutions that provide high potency when applied to prodine (the compound closest to 3-methyl ketobemidone)..

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H should add that it's likely that the (3S,4S) stereoisomers is likely to be an agonist, but much less potent. So in practice the key is to remove just 1 stereoisomer.

I do not see this as a practical target, but it is of value when understanding the stereoisomers as they apply to phenolic opioids.

 

[Fertile]

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Now, every book that details the classes of opioid including the QSAR states 'phenolic and non-phenolic opioids bind at different sites'.
So, IF the (3R,4R) isomer of methylketobemidone IS an agonist, the QSAR of related compounds would presumably be more potent, likely x7.5 x more potent. Not practical because resolution would be impractical BUT the other compound I highlighted conveniently supports differing N-substitution to whit the N-phenylethyl and the various N-substitutions highlighted in fentanyl analogues. Not because the 2 are chemically similar but because PubChem provides such examples with their MOR activity.

Not practical, but of value t those seeking to construct QSAR data.

I mean, 25mg of ketobemidone is reputed to be as potent as 60mg of morphine making it a usefully potent compound.

 

[MedicinalUser247]

You know, the other half Opiate half Anesthetic Dissociative I was looking at was Ketobemidone, but I don't know how strong a Dissociative it actually is. It says the Opiate has some NMDA antagonism, but I don't know by how much. If it had equal effects that would be interesting.

 

[negrogesic]

Acetoxymethylketobemidone (O-AMKD) was available for sale not long ago. Almost bought some, but then decided it wasn't a great idea (I would have blasted through it compulsively, and I try to avoid opioids these days). Plus, heard it was only so so, and it was fairly low potency.

 

[MedicinalUser247]

If I wanted to create an analog it would probably be a cross between ketobemidone and ketamine. So, I would creat a hybrid between the two. You just have to take a look at the molecules and think. Ketobemidone 1-(4-(-3-Hydroxyphenyl)-1-methyl-4-piperidyl)propan-1-one and Ketamine (RS)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone. Its kind of like a puzzle.

 

[negrogesic]

If I wanted to create an analog it would probably be a cross between ketobemidone and ketamine. So, I would creat a hybrid between the two. You just have to take a look at the molecules and think. Ketobemidone 1-(4-(-3-Hydroxyphenyl)-1-methyl-4-piperidyl)propan-1-one and Ketamine (RS)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone. Its kind of like a puzzle.

It's not quite as simple as mashing two molecules together and expecting them to retain their individual activity. As far as I can recall, I can't think of any opioid that is a pure MOR agonist (i.e., not a partial agonist) that also has high enough affinity for the NMDAR to produce simultaneously strong narcotic and dissociative effects (specifically, psychotomimetic dissociative effects).

For example, in the table below, you can see that as NMDA affinity increases, specificity for the MOR decreases (e.g., increased affinity for the KOR), which is not a desirable thing. Also, the added bulk reduces efficacy of MOR binding, which often results in these compounds behaving as partial agonists (also undesirable):



So again its not quite a simple as making a compound that is a, "cross between ketobemidone and ketamine". Conceptually, one can think of these compounds as keys with specific shapes that fit certain receptors (locks) in the brain, and as with any kind of lock, it's hard to make a key that's a perfect fit for different locks (especially when the function of those locks are very different).

 

[AlsoTapered]

Acetoxyketobeidone is purely a prodrug. Now, if someone had actually studied the class they would have found the German papers in which the ethyl ketone is replaced by an ethyl sulfone. Analgesic activity was just the same BUT since this was work from the 1950s, no information on NMDA activity...

It may well be the case that their is sufficient NMDA activity to improve overall analgesic activity, but if they produced dissociative effects like full-on NMDA antagonists, they wouldn't be usable AS analgesics except for in a very narrow field of applications.

Anyone studying NMDA antagonists should BEGIN with dizocillpine (MK-801) and identify the key moieties.

It seems no matter how often I mention that their is a VITAL relative distance and angle between the N: and the aromatic, I've NEVER seen anyone post. And those values are known with a high precision. If I could find the paper, so could anyone else... tsk, but what am I thinking about - that took me days of effort, not a moment with Google.

 

[MedicinalUser247]

Do you think it would be possible to add an extra molecule to the top of Dizocillpines chemical structure ? Or would you be unable to bind another molecule there ? Just curious.