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Useful papers on the older sedative-hypnotics

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Wollweber, H. (2000). Hypnotics. Ullmann’s Encyclopedia of Industrial Chemistry. doi:10.1002/14356007.a13_533

Hassan Y.Aboul-Enein Analytical Profiles of Drug Substances - Glutethimide Volume 5, 1976, Pages 139-187 https://doi.org/10.1016/S0099-5428(08)60318-4

The determination of (R)- and (S)-glutethimide and the corresponding 4-hydroxyglutethimide metabolises in human serum and urine using a Pirkle-type HPLC chiral stationary phase://doi.org/10.1016/0731-7085(87)80088-2

And an interesting question: https://pubmed.ncbi.nlm.nih.gov/7071114/

I note that 4-hydroxyglutethimide (metabolite of (R) glutethimide/aminoglutethimide) can be dehydrated yielding an alkene similar to piperidione. I also note that the 3,3-diethyl and the 3-ethyl-3-propyl analogues of glutethimide are known to be active. I also spotted that p-amino glutethimide is also a CYP2D6 inducer. I suppose the simplest idea would be to produce the 3,3-diethyl analogue of glutethimide since the point isn't to enter the CNS but to induce the enzyme that increases the O-demethylation of codeine/dihydrocodine/hydrocodone/oxycodone from 8-12% to ≈80%.

My best guess is that a hydroxyl that shares a C with an alkene i.e. -CH=C(OH)- is responsible for O-demethylatioin. 3,3-Diethyl-4-hydroxy-2,6(1H,3H)-pyridinedione (CAS 99709-75-8) is known. Metabolism of (R) glutethimide yields 3-Ethyl-5-hydroxy-3-phenyl-2,6(1H,3H)-pyridinedione.
 
Could some of those glutethimide derivatives be teratogens like thalidomide?
 
A very good question. Well, looking at the (safe) drugs developed from thalidomide, it's the phthalimide rather than the 2,6-Piperidinedione moiety that is altered. Specifically, the designers tend to add a metabolic handle to make it easy for the body to remove. In fact, what thalidomide teaches us is that thalidomide exists as a tautomer as does methyprylon. A quick research reveals that while (5S)-3,3-Diethyl-5-methyl-2,4-piperidinedione has been assigned a CAS number, the (5R) stereoisomer has not.

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A close examination of the metabolism of (R) glutethimide also reveals that one of the metabolites is ring-hydroxylation and then dehydration forming an alkene (memories of pyrithyldione).

I am still reading all I can find because each fact has to be teased out like methyprylon's trans isomer seeming to be the active one and that teutomerism exists in all of these rings... oh, and of course that as well as p-NH2, almost every (pseudo)halogen produces a p-amino glutethimide analogue that is active.

I also discovered that several analogues of glutethimide are known and are active. The ethyl,n-propyl, the methyl-ethyl but it seems that asymmetry is important, possibly just to ensure that the metabolism produces the active CYP2D6. Since this metabolite is only 2% of the excreted, it would appear to be quite active. Someone, somewhere replaced the -OH with an -OCH3 which I found jolly interesting. I suspect that in one conformation, the -OH & -OCH3 (the 3 position of codeine derivatives) are swapped and the -CH3 is transferred to the nitrogen.

I apologise, it's about 7AM and I have been searching through all of this, trying to spot little tell-tale signs that might allow us to design a CYP2D6 enhancer AND trying to rewrite some Cortex-M0+ subroutines to make the most humble ARM processor decode MP3 in real-time.

Sorry, more clues. Page 146 of the book Medicinal Chemistry by By Ashutosh Kar quote: 'The metabolism of methyprylon is found to be extensive, and the drug is an enzyme inducer'.

Page 211 of the book The Practitioner's Guide to Psychoactive Drugs edited by Ellen L. Bassuk, Stephen C. Schoonover, Alan J. Gelenberg 'methyprylon is almost completely metabolised by the liver where it stimulates the microsomal enzyme system'

But the most telling was that in 1984, a clandestine chemist was caught making both glutethimide and methyprylon. Given the low potency of the drugs, like methaqualone, their must have been a ready market for the product.
 
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Some 2,6-piperidinediones with a substituent only at the nitrogen atom are also active (but possibly only at an impractically high dose level).

pubmed.ncbi.nlm.nih.gov

Central effects of N-substituted derivatives of 2,6-dioxopiperidine in mice - PubMed

Pharmacological activities of N-allyl, N-benzyl and N-o-xylyl derivatives of both 2,6-dioxopiperidine (DOP = glutarimide) and 4-ethyl-4-methyl-2,6-dioxopiperidine [bemegride(BG)] were studied in mice. Convulsant activity, hypnotic activity, anticonvulsant activity, acute toxicity and...
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
 
Well, I have noticed that a good 90% of CNS depressants have an amide function in them somewhere. Those that don't seem to have an alcohol or chloride (-Cl acting as an alcohol bioisostere with better LogP in these cases)?
 
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Now, given that the CYP2D6 enzyme is only expressed in liver tissue so the questions are:

1- Is one or both of the glutethimide isomers is a CYP2D6 inducer?
2- Is one of both of the metabolites a CYP2D6 inducer?

Given that p-aminoglutethimide is ALSO a CYP2D6 inducer, but it's metabolite p-hydroxyglutethimide (also metabolite of (-/R) glutethamine) is NOT(https://pubmed.ncbi.nlm.nih.gov/6689274/) is an inducer, it seems logical to consider that the (+/S) isomer or it's 4-hydroxy metabolite (4-Hydroxy-2-ethyl-2-phenylglutarimide) are responsible. The latter is particularly interesting since it introduces a further chiral centre and I suggest that it's a tautomer. I know a-hydroxyamides exist as tautomers but have not for an example of a 3-hydroxy-piperidine 2,4-dione.

It's purely a guess but I think that the 4 -OH gluteramide, having an a-OH ketone
 
It has also been noted that 4-hydroxyglutethimide is twice as potent as it's parent compound. it the mouse model. Apparently only 1 isomer exists so no tautomerism. It is a shame that glutethimide was taken off the market before the technology to fullly elucidate it's metabolism was available. One thing is for certain, the -OH certainly lowers the LogP of the compound and will therefore not concentrate in fatty tissue (such as the brain) as much. I also note that the 2-ethyl-2-propyl analogue has also been made and tested. Sadly, no work has been carried out on this interesting compound...

https://doi.org/10.3181/00379727-156-39964

Presuming that the ethyl-propyl analogue also has CYP2D6 activity, it's partition (LogP) should be even more favourable.
 
clubcard said:
Wollweber, H. (2000). Hypnotics. Ullmann’s Encyclopedia of Industrial Chemistry. doi:10.1002/14356007.a13_533

Hassan Y.Aboul-Enein Analytical Profiles of Drug Substances - Glutethimide Volume 5, 1976, Pages 139-187 https://doi.org/10.1016/S0099-5428(08)60318-4

The determination of (R)- and (S)-glutethimide and the corresponding 4-hydroxyglutethimide metabolises in human serum and urine using a Pirkle-type HPLC chiral stationary phase://doi.org/10.1016/0731-7085(87)80088-2

And an interesting question: https://pubmed.ncbi.nlm.nih.gov/7071114/

I note that 4-hydroxyglutethimide (metabolite of (R) glutethimide/aminoglutethimide) can be dehydrated yielding an alkene similar to piperidione. I also note that the 3,3-diethyl and the 3-ethyl-3-propyl analogues of glutethimide are known to be active. I also spotted that p-amino glutethimide is also a CYP2D6 inducer. I suppose the simplest idea would be to produce the 3,3-diethyl analogue of glutethimide since the point isn't to enter the CNS but to induce the enzyme that increases the O-demethylation of codeine/dihydrocodine/hydrocodone/oxycodone from 8-12% to ≈80%.

My best guess is that a hydroxyl that shares a C with an alkene i.e. -CH=C(OH)- is responsible for O-demethylatioin. 3,3-Diethyl-4-hydroxy-2,6(1H,3H)-pyridinedione (CAS 99709-75-8) is known. Metabolism of (R) glutethimide yields 3-Ethyl-5-hydroxy-3-phenyl-2,6(1H,3H)-pyridinedione.
Click to expand...

Interesting, Im not a scientist but since Im depending on sedatives/hypnotics because of chronic insomnia.
I always find it interesting to try and learn about old and new sleep-aids/medicines.

And please,

Dear Santa!
I would really like to find a better alternative to benzos and z-analogs, something that would function as an anxiolytic, but mainly function like a strong hypnotic with a long enough half-life to keep me sleeping through the whole night, preferably leave me rested the next day and ready to rock the world, with out any hang-over effect and low potential for development of tolerance. 🙏😇❤
 
Pharmazie 82 Jan;37(1):69.
[Is pyrithyldione (Benedorm) an enzyme inducer (author's transl)]

I do not have access to the paper above BUT it is referenced in the 'enzyme inducer' section of 'Cumulated Index Medicus, Volume 23'.

I mention this because a metabolite of 4-hydroxyglutethimide is the product of dehydration to 3-Ethyl-3-phenyl-2,6(1H,3H)-pyridinedione

ibb.co

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Which, interestingly, has not 1 but 2 CAS numbers: 14149-36-1 [RN] 5-21-11-00298 [Beilstein]

DOI: 10.1021/jm00241a019 covers the 14 metabolites of glutethimide!

It's an interesting problem... I would certainly like to hear from someone who has a better handle on mecanistic studies BUT if the ethenyl moiety is important (as the paper at the top suggests) then we will have a pretty good idea.

 
Here's a curious article that claims that benzylacetone, found in some plant sources, has a sedative effect when inhaled. It is also compared to the sedative effect of acetophenone and benzaldehyde, the former of which was used as a sedative-hypnotic in the 19th century. I believe the effect of acetophenone could have a mechanism similar to general anesthetics like diethyl ether with high lipid solubility making a small dose effective, but I'm not that sure about the other compounds in this paper.

Sedative Effects of Inhaled Benzylacetone and Structural Features Contributing to Its Activity

Access full-text academic articles: J-STAGE is an online platform for Japanese academic journals.
www.jstage.jst.go.jp www.jstage.jst.go.jp
 
https://doi.org/10.1016/S0099-5428(08)60318-4

The above paper notes that the (+) isomer of glutethimide is 2-3 times more potent than the (-) isomer. Interesting, 4 hydroxy glutethimide is twice as potent as it's parent and the -OH is chiral. In cases of overdose, 4-OH glutethimide accumulated. It's LogP will be lower than it's parent so INCREASED activity is interesting.
 

The above paper shows that in the rat model, glutethimide prevents the gluconation of morphine. I, for one, believe that it's actually the 4-hydroxy metabolite that is responsible being a 'sacrificial' gluconation pathway. It should be noted that only the (+) (R) isomer of glutethimide forms 4-OH glutethimide.

It isn't definitive and in a way it's a shame that it's an active metabolite which is why I am still interested by Pyrithyldione because it may also be a CYP2D6 enhancer since it also forms a -OH metabolite. I find it fascinating that clandestine labs were churning out glutethimide until codeine became harder to obtain. Of course, if it produces a similar action with hydrocodone & oxycodone (the latter costing $1-$2/mg) then it might prevent people from moving on to injecting opioids.
 
Pyrithyldione IS an enzyme inducer so comparison with piperidione would be awfully helpful. if so, methyprylon would also be worth looking at BUT only glutethimide has the 3,3-dialkyl piperidine-2,6-dione moiety.
 
black seed oil is the best inducer imo
 
Well, science has spent 50 years trying to find a CYP2D6 inducer, so what is it in black seed oil that has eluded generations of medicinal chemists?
 
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