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Dextromethorphan N-Oxide Hydrochloride

PsychedelicTs

PsychedelicTs

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Jan 6, 2015
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Has anyone tried this N-Oxide Hydrochloride form of DXM? I've been using it in the standard Hydrobromide form for years now, but today I discovered a company selling this form of DXM. I have found very little info on it so I thought I might see if any bluelighters have tried it. What do you guys think? Promising or should I stick with the good ol' HBR form?
MM0033.11.jpg


Molecular Formula: C18 H25 N O2 . Cl H
 
I think at the very least it'd be an intermediate towards N-demethylation, am not even sure what that "nor-DXM" would be like (my best - wild - guess is that it would not be good for psychoactivity at all). I couldn't really answer the question without saying that but that is about as much synthesis discussion as we are going to allow... (just now when it was still a PD thread)

If the company is asking huge prices for it (cause of needed purity), or is selling a lot of other chemicals that are not really known to be psychoactive the above is more likely. Indeed I myself am finding sources with big prices for tiny amounts. When you see that, they are e.g. reference samples. I think that is quite enough source discussion perhaps, but browsing reference samples is a bit of a rookie mistake.

The polarity is not always good for brain permeability / bioavailability, but clearly as demonstrated by N-oxides of some antidepressant drugs it can actually be a beneficial modification.
I guess cause it's locally stabilized / neutral at the N-oxide?

Apart from that, beats me :?

Better suited for NSP, so moving there out of PD.
 
The compound is a zwitterion so it might be a winner, honestly I've never seen a non pyridine or tetrahydropyridines N-oxide's bioavailability.. I'm questionable if this exists because it could be a hydroxylamine then again who knows. Ask for a gc ms or a nmr otherwise I doubt it... I wonder if it will be demethylated anyway but then again cytochromes are promiscuous..

Excellent question though but without spectroscopy confirmation and cost price analysis I'm clueless..
Zedsdead
 
There are actually no papers confirming routes of morphine-N-oxide metabolism and the only paper I could find is a few decades old. It may be partially metabolised into morphine with the rest being glucuronidated and rapidly excreted. Dextromethorphan-N-oxide can't be directly glucuronidated so perhaps the conversion to dextromethorphan would be a bit more effective.

Also, the question is the activity of dextromethorphan-N-oxide on its own, but I too doubt that it could first pass the blood-brain barrier at a sufficient rate. BTW, normetazocine has a higher affinity towards NMDA receptors than metazocine (I think values may be found through Pubmed), so nor-DXM and nor-DXO may have a role in dissociative effects.
 
Zeds(NCO2CH2CH3)2 said:
The compound is a zwitterion so it might be a winner, honestly I've never seen a non pyridine or tetrahydropyridines N-oxide's bioavailability.. I'm questionable if this exists because it could be a hydroxylamine then again who knows. Ask for a gc ms or a nmr otherwise I doubt it... I wonder if it will be demethylated anyway but then again cytochromes are promiscuous..

Excellent question though but without spectroscopy confirmation and cost price analysis I'm clueless..
Zedsdead
Click to expand...

Can zwitterions cross the BBB? Normally charged species are excluded but I'm not sure how it works with zwitterions.
 
Well zwitterions vary, there are many types, they are essentially weak inner salts, interacting by Van Der waals forces. Many examples exist I.e 4-ho dmt (psilocin) ( note that at physiological pH the dimethyl amine is protonated and forms an inner association with the 4-hydroxy) , but what about psilocibin then? It's difficult some of the compounds are recognized by the transporters as amino acids, others through endocytotic means..

Google endocytosis blood brain barrier

Very peculiar, many factors at work, nothing is very clear cut. Most likely this drug is active only via parenteral administration. If taken Orally it will be excreted too fast. This drug may also be implicated in reactive oxygen or reactive nitrogen species.

Other examples close to this include morphine n - oxide, but this compound has not been abused to my knowledge so far. It is a common metabolite. I am unsure if it is glucuronidated or sulfonated however .

This thread attracted Chinese sharks no doubt..

Zedsdead
 
Zeds(NCO2CH2CH3)2 said:
Well zwitterions vary, there are many types, they are essentially weak inner salts, interacting by Van Der waals forces. Many examples exist I.e 4-ho dmt (psilocin) ( note that at physiological pH the dimethyl amine is protonated and forms an inner association with the 4-hydroxy) , but what about psilocibin then? It's difficult some of the compounds are recognized by the transporters as amino acids, others through endocytotic means..

Google endocytosis blood brain barrier

Very peculiar, many factors at work, nothing is very clear cut. Most likely this drug is active only via parenteral administration. If taken Orally it will be excreted too fast. This drug may also be implicated in reactive oxygen or reactive nitrogen species.

Other examples close to this include morphine n - oxide, but this compound has not been abused to my knowledge so far. It is a common metabolite. I am unsure if it is glucuronidated or sulfonated however .

This thread attracted Chinese sharks no doubt..

Zedsdead
Click to expand...
I didn't think the amine in psilocin is a strong enough base to deprotonate the hydroxy group.
 
No deprotonation just van Der waals association between the oxygen OH and the hydrogen of the H(ch3)2R, psilocibin does this as well between its phosphoryloxy group through the charged oxygen it can associate with the positive nitrogen of the dimethyl ammonium ion.. It's a common thermodynamic trend, how molecules minimize their free energy in solutions
 
Zeds(NCO2CH2CH3)2 said:
No deprotonation just van Der waals association between the oxygen OH and the hydrogen of the H(ch3)2R, psilocibin does this as well between its phosphoryloxy group through the charged oxygen it can associate with the positive nitrogen of the dimethyl ammonium ion.. It's a common thermodynamic trend, how molecules minimize their free energy in solutions
Click to expand...

My confusion stems from the fact that you said psilocin can form a zwitterion. Wouldn't that require the OH to be deprotonated? I thought that zwitterions are neutral by definition.
 
I seriously doubt that morphine-N-oxide or dextromethorphan-N-oxide could pass the blood-brain barrier in an appreciable amount. Their hydrophilicity is higher in respect to parent compounds, and even secondary amine analogues like normorphine have a much higher hydrophicility, so I can imagine an N-oxide with formal charges will be even more of a problem here.

Also, I'm not really sure if amine-N-oxides may be viewed as zwitterions as there are formal charges on nitrogen and oxygen atoms and no ions are formed.
 
Psilocin and psilocibin can form zwitterions the OH does not need to be protonated I explained the interaction above.

For fast information read Wikipedia zwitterions

Otherwise amine n oxides may or may not be zwitterions, trimethyl amine N oxide is arguably a zwitterion ion but not. This compound functions as an osmolyte in fish interestingly enough.

Zwitterions are just inner salts, more thermodynamically favorable in solution which can influence their entry across membranes as their free energy is much lower because they are not blatantly charged. For example charged ionized species have a difficult time crossing membranes unless they undergo intermolecular or intrrmolecular zwitterionic interactions. Other molecules use amino acid transporters to enter, others use endocytotic means.

Amine n oxides do not enter the brain as far as I know, but then again I do not know if anyone has even tried. No drugs of abuse have been amine n oxides and this may as well be an excellent question. Thermodynamics...

Zedsdead
 
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Zeds(NCO2CH2CH3)2 said:
Psilocin and psilocibin can form zwitterions the OH does not need to be protonated I explained the interaction above.

For fast information read Wikipedia zwitterions

Zwitterions are just inner salts, more thermodynamically favorable in solution which can influence their entry across membranes as their free energy is much lower because they are not blatantly charged. For example charged ionized species have a difficult time crossing membranes unless they undergo intermolecular or intrrmolecular zwitterionic interactions. Other molecules use amino acid transporters to enter, others use endocytotic means.

Zedsdead
Click to expand...

Psilocin does not fit the definition of a zwitterion according to the source you listed (wikipedia). I'll quote directly:

"a zwitterion...is a neutral molecule with a positive and a negative electrical charge, though multiple positive and negative charges can be present. Zwitterions are distinct from dipoles, at different locations within that molecule. Zwitterions are sometimes also called inner salts. Unlike simple amphoteric compounds that might only form either a cationic or anionic species depending on external conditions, a zwitterion simultaneously has both ionic states in the same molecule."

So if psilocin does not simultaneously contain both a negative and a positive charge then it is not a zwitterion. Obviously the amine in psilocin can be protonated but for psilocin to form a zwitterion some other part of the molecule would have to be deprotonated.
 
So based on what I'm reading, (ignoring facilitated transport mechanisms) we should expect n-oxide compounds like Dextromethorphan N-Oxide Hydrochloride to passively diffuse through membranes more readily than a normal charged species (because the positive and negative charges mask each other), but still less readily than a compound without ionic charge.

Does that sound like a reasonable interpretation? Normally I just use the heuristic "charged compounds don't cross the BBB without a facilitated transport mechanism", so I'm trying to figure out how to adjust that assumption for compounds like these.
 
endotropic said:
So based on what I'm reading, (ignoring facilitated transport mechanisms) we should expect n-oxide compounds like Dextromethorphan N-Oxide Hydrochloride to passively diffuse through membranes more readily than a normal charged species (because the positive and negative charges mask each other), but still less readily than a compound without ionic charge.

Does that sound like a reasonable interpretation? Normally I just use the heuristic "charged compounds don't cross the BBB without a facilitated transport mechanism", so I'm trying to figure out how to adjust that assumption for compounds like these.
Click to expand...

The N-oxide apparently doesn't have a charge so it may be able to diffuse into the brain. The downside is that it is impossible to predict what its pharmacodynamics will be like, and it is potentially going to be a substrate for demethylation by CYP450.

It is probably being sold as a reference standard, either to facilitate analysis of DXM purity or for use as an internal standard.
 
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