Anyone know the pharmacodynamic effect of halomorphine derivatives?

[Illuminateur]

Both bromomorphine and chloromorphine have been manufactured, but at the "meta to phenolic hydroxyl group" position. I can't find any pharmacodynamic data on the products though. Presumably that wasn't the point of synthesising them. But we do know that many halogenated amphetamines and amphetamine derivatives are biologically active.

In particular though, I'd like to know what would happen if you replaced one of the 3,6 2ndary alcohols with an F, Cl, Br, I... say with a Lucas Reagent (conc. HCl, ZnCl₂). The halogenated derivative would still have lone pairs in the appropriate position, and should react similarly, although be far less protic/hydrophilic, and therefore better absorbed.

Furthermore, halides X^- are significantly better leaving groups than ^-OH, which might even make them prone enough to nucleophilic substitution with acetyl groups with merely glacial or concentrated acetic acid rather than the more difficult to obtain acetic anhydride. But there would likely be some halogenated derivate left over so I would not want to try this without first obtaining some information on the potential toxicity or pharmacological effect. 4FA seems to be fairly non-toxic, whereas 4-chloroamphetamine does not seem so nice. The 2Cs seem to do pretty well, but that could be because the dosages are significantly lower.

Just curious, figured if anyone knew, I'd probably find them here.

 

[sekio]

The 6-halomorphine/halocodeines are known compounds called codides and halomorphides, for instance, alpha-chlorocodide. It's hard to make them selectively because morphine and codeine undergo a number of side reactions like acid catalyzed rearrangement to apomorphine, destruction of the 4,5 epoxide ether ring, halogenation of the aromatic ring at the meta-position, fission of the methyl ether with things like HBr/HI converting codeine to morphine etc.

Chloromorphide is said to be 10x more potent than morphine in an isolated pure form, but it's difficult to prepare in a selective fashion. I would imagine.

Another two interesting chemicals are heterocodeine (6-methoxymorphine - 50 to 100x stronger than codeine, so 5-10x stronger than morphine) and isocodeine (codeine with the 6'alcohol inverted stereochemically - I don't have a figure for potency).

Clearly 6 position substitution leads to interesting stuff - 6-monoacetylmorphine is a potent narcotic, thought to be the main active metabolite of heroin.

6-acetylcodeine however is a very strong histamine releaser, more so than any other narcotic, and cannot be used IV/IM/smoked because it results in anaphylaxis, generalized itching and redness, and pulmonary edema.

The codeinone/morphinone enol ethers thebaine and orpiavine are also not considered effective narcotics for this same reason. It also explains why synthetic opioids like fentanyl cause less itching than codeine or morphine - all the phenanthrene opioids cause histamine release. Even DXM causes itching.

Alpha-iodocodide is theorized to be one of the intermediates or side products from clandestine desomorphine synthesis. I know that ring-halogenated derivatives of morphine have been made as radiotracers too (1-iodomorphine), but I'm not sure they share agonist activity.

Synthesis discussion is not allowed so let's not get into specifics though.

 

[Limpet_Chicken]

Not too sure about oripavine, but I'm fairly sure that thebaine is not just problematic due to histamine release, IIRC it
acts on strychnine-sensitive glycine receptors as an antagonist, rendering it a convulsant.

Although I have a hunch it might have something to do with the stimulating qualities raw opium, or a full-spectrum isolate of it possesses, a quality that in my experience with both morphine and codeine, compared to opium, the former two do not possess. Strychnine itself, has been used as a stimulant in small doses. So extrapolating from that, I'd guess thats at least one of the things giving opium/pod tea its unique qualities.