Pholcodine --> morphine

[miconorphine]

about 1% of Pholcodine is turned into morphine, does anyone know the enzyme responsible for this ?

 

[MurphyClox]

This is not published to my best knowledge, but most probably happens by CYP2D6 and/or CYP3A4.

- Murphy

 

[seep]

It's p.o., so is it possible that the ether is cleaved by the stomach's acidic environment?

 

[surrеalist]

It's p.o., so is it possible that the ether is cleaved by the stomach's acidic environment?

What you are thinking of is boiling with HI or HBr, not body temp with weak HCl (stomach acid). Cl is only slightly less electronegative than the oxygen in the ether, so there is not enough initiative for the oxygen to steal a hydrogen from the acid to form a more preferable -OH group, unlike stealing a hydrogen from HI or HBr, since I and Br are less electronegative and won't complain being stuck in a leaving group with carbon, which is less electropositive then hydrogen.

Oh but that is not a synthesis because there is another ether in codeine/pholcodine/morphine, and an attempt of the above would give really useless products (apomorphine and the like).

 

[lolwhatzdrugs]

What you are thinking of is boiling with HI or HBr, not body temp with weak HCl (stomach acid). Cl is only slightly less electronegative than the oxygen in the ether, so there is not enough initiative for the oxygen to steal a hydrogen from the acid to form a more preferable -OH group, unlike stealing a hydrogen from HI or HBr, since I and Br are less electronegative and won't complain being stuck in a leaving group with carbon, which is less electropositive then hydrogen.

Oh but that is not a synthesis because there is another ether in codeine/pholcodine/morphine, and an attempt of the above would give really useless products (apomorphine and the like).

I must say dear sir, this is the best 'first post' that I've found yet!

 

[Detrevni]

^Agreed. Welcome to Bluelight!

 

[surrеalist]

Thanks, I re-edited it several times. And sorry to dissapoint you guys but I actually had an account here before with 70 posts maybe before I quit posting and lost the email it was linked to. But thanks. You should have seen the fight I had to go through to register with this username.

 

[seep]

While we're on the subject of exotically-metabolized morphine analogues/prologues:

Any sources for the half life of myrophine? Or ROA? Would the post-activation high be distributed over the course of several weeks, as it is with other decanoates?

 

[surrеalist]

Removing the 3-benzyl ether would be a great idea, since it has to be cleaved by the liver (and the liver will shred through the 6-ester so myrophine will never be active prior to liver metabolism). Without the 3-benzyl, the myristic acid ester would probably be cleaved by plasma esterases anywhere, which would allow it to cross the BBB before turning into the less-lipophilic morphine, allowing for a better CNSNS ratio.

Then, either 3,6-myristil morphine or just 6-myristil morphine would probably be superb. The 6-myristil might be active even before deacetylation, like 6-MAM, and similarly might be an order stronger than morphine itself.

 

[lolwhatzdrugs]

While we're on the subject of exotically-metabolized morphine analogues/prologues:

Any sources for the half life of myrophine? Or ROA? Would the post-activation high be distributed over the course of several weeks, as it is with other decanoates?

What exactly is the effect of the fatty acid? Will it slowly diffuse into circulation and metabolize to morphine?

It seems to be one of those drugs where any search outside wikipedia only lists it as what classification it is controlled in.

Maybe there's a good reason the don't want anyone to give it a good try.

 

[seep]

^I think they list it for historical reasons.

What exactly is the effect of the fatty acid? Will it slowly diffuse into circulation and metabolize to morphine?

Once when I was hospitalized, the fuckers gave me a shot of haloperidol decanoate cuz I wasn't med compliant. IM. Glute. The idea: it is very lipophilic and therefore stored in fat and gradually activated by esterases. The Haldol lasted 3 or so weeks and wasn't pleasant. It spooked the hell out of me. I haven't had a psychotic episode since.

I wonder if removing the 3-benzyl ether would be a great idea

Yeah but not because of activity of the 6-decanoate. See abstract:

NSFW:

1. Int J Pharm. 2008 Apr 2;353(1-2):95-104. Epub 2007 Nov 17.

The delivery and antinociceptive effects of morphine and its ester prodrugs from
lipid emulsions.

Wang JJ, Sung KC, Yeh CH, Fang JY.

Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan.

Long-acting analgesia is critical for patients suffering from long-acting pain.
The purpose of this study was to develop lipid emulsions as parenteral drug
delivery systems for morphine and its ester prodrugs. Morphine prodrugs with
various alkyl chain lengths, including morphine propionate (MPR), morphine
enanthate (MEN), and morphine decanoate (MDE), were synthesized. The prodrugs
were stable against chemical hydrolysis in an aqueous solution, but were quickly
hydrolyzed to the parent drug when exposed to esterase and plasma. Lipid
emulsions were prepared using phosphatidylethanolamine (PE) as an emulsifier,
while squalene was used as an inner oil phase. Drug release was found to be a
function of the drug/prodrug lipophilicity, with a lower release rate for
more-lipophilic drug/prodrugs. The inclusion of morphine and its prodrugs into
lipid emulsions retarded their release. Lipid emulsions, which incorporated
cholesterol, generally exhibited a drug/prodrug release comparable to that of
emulsions without co-emulsifiers. Pluronic F68 (PF68) further slowed down the
release of morphine and its prodrugs from the emulsions. The antinociceptive
activity through the parenteral administration of these emulsions was examined
using a cold ethanol tail-flick study. Compared with an aqueous solution, a
prolonged analgesic duration was detected after application of the drug/prodrug
emulsions. Incorporation of co-emulsifiers such as PF68 and cholesterol further
increased the duration of action. The combination of prodrug strategy and lipid
emulsions may be practically useful for improving analgesic therapy with
morphine.

PMID: 18158222 [PubMed - indexed for MEDLINE]

Coolest thing about that for me is the elaborateness of the emulsion

 

[lolwhatzdrugs]

Once when I was hospitalized, the fuckers gave me a shot of haloperidol decanoate cuz I wasn't med compliant. IM. Glute. The idea: it is very lipophilic and therefore stored in fat and gradually activated by esterases. The Haldol lasted 3 or so weeks and wasn't pleasant. It spooked the hell out of me. I haven't had a psychotic episode since.

So then the myrophine molecule would have the same gradual release? You could maintain a constant morphine high for 3+ weeks?


It seems like even if this were possible, It would have to increase the dose slowly as well since tolerance would seem to develop rapidly, being exposed to morphine 24-7 and all.

 

[miconorphine]

back to Pholcodine

it has some intresting metabolites including

6-mam
morphine
codeine
dihydrocodine
Nalorphine

would the conversion to morphine from Pholcodine by via o-dealkylation, which enzyme causes o-dealkylation?

if so could you not induce these

 

[miconorphine]

just found this

Nor-P, desmorpholino-hydroxy-P, nor-desmorpholino-hydroxy-P, hydroxy-P, oxo-P, nor-oxo-P and morphine in traces. Therefore, the following four partly overlapping phase I metabolic pathways can be postulated: N-demethylation, N-desalkylation at the morpholino ring followed by reduction of the resulting aldehyde to the desmorpholino-hydroxy metabolite, oxidation of the morpholino ring to the hydroxy and oxo metabolite, and O-desalkylation to morphine.

http://grande.nal.usda.gov/ibids/index.php?mode2=detail&origin=ibids_references&therow=218671