acetylation or diacetylation of certain opioids

[Canis aureus]

About that... and some opioids.

As all knows heroin is diacetylated morphine. And that those acetyl groups or that acetylation causes it to cross the BBB much more efficiently.

Heroin or morphine is not the only opioid which could be acetylated in such way (and this topic has been discussed here to some extent). I just don't remember did previous discussion mention or was it discussed about what or which else opioids could be acetylated successfully and with the similar increase in psychoactivity potency...? So, do you know which opiods?

Oxymorphone was one... are there others?

 

[MattPsy]

All short-chain esterifications (ethyl/acetyl, in this case) will improve the potency of opioids AFAIK.
Some in particular, like adding a cinnamyl ester to the -14 hydroxyl group on oxycodone/oxymorphone, can improve the potency through means other than simple lipophility changes, by acting as additional binding moieties - the -14 cinnamyl ester on oxycodone can increase potency to over 50 times that of morphine, for instance.

 

[Jamshyd]

^ Are you sure? I could swear I read that ethylmorphine is much less potent than morphine...

 

[Beenhead]

does ethyl morphine have an additional short chain ester on it?

 

[sarbanes]

Jamshyd,

You are correct, the phenol is always more potent. Heroin is unique, although is is virtually more potent than morphine, the reason why is due to its highly lyphophyllic properites, combined with a good leaving grp in the brain (acetyl). Still, the active is the phenol, and morphine is as active as morphine.

 

[MattPsy]

Ethylmorphine where the ethyl ester is attached where?
Yeah morphine is one of the odd ones out since both of it's OH's (positions 3 & 6 isn't it?) are exposed. The -one's on the other hand have the OH that doesn't directly participate in binding (position 6 isn't it? I forget...) as a ketone instead.

 

[mad_scientist]

Ethylmorphine has an ethyl ether at the 3-position, i.e. like codeine but with ethoxy instead of methoxy. Big difference in effects between esters and ethers, as esters are rapidly hydrolysed to the free phenol, whereas ethers are hydrolysed slowly and incompletely, if at all.

O-acetylhydromorphone has been made and was researched for human use, although it never ended up being marketed to my knowledge. Would probably be lots of fun though! Another good one to try would be O-acetylketobemidone. And of course, dihydroheroin (i.e. diacetyldihydromorphine) not only exists but is even used in medicine in some places (Germany I think?)

Like sarbanes says, the active form of these drugs will always be the free phenol, but seeing as the acetyl esters of phenols are rapidly hydrolysed in vivo, it might well lead to an apparant increase in potency if masking the OH group leads to increased bioavailability due to increased lipophilicity as it does with morphine --> heroin.

Another thing to try would be different esters than acetyl. Di-(n)-propanoylmorphine and Di-(n)-butanoylmorphine have been made, with the propanoyl ester being either equipotent or more potent than heroin depending on which reference you read, but the butanoyl ester dropped down in activity again and was actually less potent than morphine.

Also theres nicomorphine of course, morphine-3,6-dinicotinate, which is somewhat superior to morphine (although whether it is better than heroin or not is harder to say).

So there is some potential in making novel esters of opiates/oids, but only certain substitutions will result in an improved drug, it depends mainly on whether the bioavailability or blood-brain barrier penetration of the parent compound is hindered by its lipophilicity, and whether the particular ester used is hydrolysed sufficiently rapidly and efficiently to release the free phenol form of the parent compound once it has entered the brain.

 

[morphiquet]

i can guarantee you that there is no dihydroheroin on the (legal) market in germany. though interestingly, our lovely neighbour country austria uses nicomorphine therapeutically.

 

[MattPsy]

So why was ethylmorphine even mentioned if it's not an esterified opioid? Big difference. Esters will be hydrolyzed whereas ethers will not undergo modification in the brain.
Yeah I seem to remember that the dipropanoyl ester of morphine was the most potent per weight, it striking the best balance between lipophilicity, onset of action (it dissolves nicely still, like diacetylmorphine/heroin, so you can IV it, unlike some of the longer chain esters), and useless molecular weight (the carboxylic acid part just gets removed, so it's just a carrier weight).
I want to try 3-propanoyl 14-cinnamyl oxymorph-6-methylene (I don't know how to name it properly, gah). I bet it'd be reeaaalll nice, and very potent . Or just the -one.

 

[Jamshyd]

^ My mistake. I did not pay attention to the ester vs. ether problem .

 

[Canis aureus]

OK, interesting.

I was thinking primarily about diacetylhydromorphone and diacetyloxymorphone... And that could there be possibility to acetylated etorphine or dihydroetorphine in similar manner?

 

[MattPsy]

^ diacetylhydromorphone cannot exist. There's only one free hyroxyl to esterify! So, you can have 3-acetyl-hydromorphone.
As for the etorphine, sure, you can have a mono or di acetylated derivative, although making the mono-acetylated one would be tricky! Not sure of the optimum placing of the single acetyl in the mono case, though!
(On a different note entirely, can anyone explain any theories as to why etorphine is so ridiculously potent compared to morphine? Is that bridge from the -6 position to the other side of that 6-membered ring the most important bit, or the other modification? I hadn't even heard of it till now, ekk ))

 

[Canis aureus]

I just like the idea of acetylation "vehicle" which brings some molecule through/across BBB.

But hey, if diacetyloxymorphone could be possible, why the same about hydromorphone wouldn't work? I don't know but oxymorphone was possible to diacetylated via its enol tautomer (making there two hydroxyl groups identical to that of morphine's two hydroxyls)... So if there could be enol tautomer also of hdromorphone, there could be diacetylation also.

In etorphine or dihydroetorphine there could not be such...

 

[Ham-milton]

3-acetyl-hydromorphone is Paralaudin, as I recall. I posted about it @ ophile a few days ago.

but yeah, you can't have a diacetyl w/ only one free hydroxyl

unless my understanding of chemistry is way off.

 

[Canis aureus]

Let me show you...

This is actually F&B's formulation (hopefully he doesn't get mad, lol)

This is the way to make two hydroxyl groups. And is it possible to form enol tautomer of also hydromorphone?

 

[Canis aureus]

And paralaudin or whatever, is diacetyldihydromorphine not diacetylhydromorphone!

 

[Ham-milton]

that's the oxymorphone derivative, not the hydromorphone. And I can't say if it's possible, if it is it'd be really fucking difficult.

 

[Ham-milton]

for some reason I can't edit my post. Yeah, I realized that after I posted.

 

[MattPsy]

Ahh yes, of course, the enol . My bad! yeah, that'd be interesting, for sure.

 

[Ham-milton]

it'd be a huge pain in the ass, methinks. I think you'd be further ahead have only one acetyl group instead of 2 for the cost and work that'd go into it.

theoretically, for a single acetyl group, would GAA work? I'm surprised a junky with a dilaudid script hasn't tried it if it would.

probably not worth it for oral use.