• N&PD Moderators: Skorpio | thegreenhand

  • Neuroscience & Pharmacology Discussion Welcome Guest
    Posting Rules Bluelight Rules
    Recent Journal Articles Chemistry Mega-Thread
    FREE Chemistry Databases! Self-Education Guide

Oxidopamine as a possible neurotoxic metabolite of 2C-D?

Volsam

Volsam

Bluelighter
Joined
Nov 19, 2016
Messages
909
2C-D
150px-2C-D_2DACS.svg.png
200px-6-Hydroxydopamine.svg.png
Oxidopamine


I was reading about metabolic pathways of 2C-D: o-demethylation in positions 2 and 5, hydroxylation in the alkyl radical in the 4th position (these two steps pretty much make 2C-D into Oxidopamine), N-acetylation, beta-hydroxylation and deamination with subsequent oxidation to carboxylic acid or reduction to alcohol.

Does that mean that at some point of it's metabolic process 2C-D may become a neurotoxic Oxidopamine (2,4,5-trihydroxyphenethylamine) that destroys dopaminergic and noradrenergic neurons in the brain?
 
Luckily for us, 6-OH-dopamine cannot cross the blood-brain-barrier. It is a "lesioning agent" that has to be injected directly into an organism's brain to exert its neurotoxic effects.

MPTP works as a neurotoxin because it is a lipid-soluble pro-drug which the enzyme MAO-B can convert to the active metabolite MPP+ in a single reaction.
I am not sure if 2C-D could form oxydopamine *at all* - from what I understand, the para-methyl isn't removed before the hydroxylation; instead, the hydroxylation happens with the methyl group still on there, giving 2,5-dihydroxy 4-hydroxymethyl phenylethylamine.
2%2C5-dihydroxy%204-hydroxymethyl%20phenylethylamine.png


And even if this metabolite were to share the neurotoxicity of 6-OH-DA, I would assume that the deamination by monoamine oxidase and subsequent oxidation to the carboxylic acid (which would likely not be taken up by the neuron, and thus lack neurotoxic effects) would take place much more rapidly than two demethylations and one hydroxylation (the substantia nigra also expresses CYP2D6 which would presumably be responsible for these reactions, but probably not to the extent that your liver does). Remember, all of these de-methylation steps have to take place inside the brain; once you've got 2 or more hydroxyl groups on there, there's probably no re-entering it.

2C-B, atleast, is overwhelmingly excreted as the non-demethylated carboxylic acid metabolite, suggesting a dominance of MAO- vs CYP-mediated metabolism.
https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1556-4029.2012.02289.x

I am assuming that more extensive O-demethylation would be taking place if the drug is ingested orally than via insufflation, but again, those metabolites would have drastically lower BBB penetration.
 
Last edited:
from what I understand, the para-methyl isn't removed before the hydroxylation; instead, the hydroxylation happens with the methyl group still on there, giving 2,5-dihydroxy 4-hydroxymethyl phenylethylamine.
Click to expand...

This is true.

If anything metabolized to oxidopamine it would be anything of the 2c-O family (as yet unseen on the market)... those would be ethers of oxidopamine.
 
The ring is to crowded for rapid O-demethylation and once 1 phenol is bare, it's LogP crashes and it the ABC transporters throw it out of the brain where it forms an addition salt with any handy anionic species for the kidneys to flush away. If the 4-OH IS formed, that COULD be neurotoxic but I don't think it's of clinical significance.
 
Last edited:
Thank you guys for clarifying that, you are all very knowledgeable and I feel grateful for such community! ;)

I'm reading more on ABC transporters now...
 
The 4-methylphenyl goes to 4-carboxyl-phenyl, which is very electron withdrawing. That's why the 4-methylphenyl drugs are often so potent, I reckon.

P.S.

2CD --> JONATHAN, in case you're interested.
 
Last edited:
Dresden said:
The 4-methylphenyl goes to 4-carboxyl-phenyl, which is very electron withdrawing. That's why the 4-methylphenyl drugs are often so potent, I reckon.

P.S.

2CD --> JONATHAN, in case you're interested.
Click to expand...

Could it be the reason (electron withdrawing) for 2C-P's long duration and strong effects? And what might be the potential metabolites of it?

I really like how the 2C-P molecule is so symmetrical looking, it just mesmerizes me... And I do love it's effects (I've had some of my best trips on it) but slightly concerned with the damage that might come with larger doses of it.



And yes, I am one of those who digs your crazy naming nomenclature, Dresden, why not?! :D
 
Dresden said:
The 4-methylphenyl goes to 4-carboxyl-phenyl, which is very electron withdrawing. That's why the 4-methylphenyl drugs are often so potent, I reckon.

P.S.

2CD --> JONATHAN, in case you're interested.
Click to expand...

Is this a very neatly disguised sarcasm here? I don't see how metabolism of para-methylphenyl moiety to para-carboxyphenyl could make that moiety a structural factor or predictor for a drug's potency, not in a general sense. Considering you could have basically any functional group somewhere else in the structure which may make the drug be metabolized to a water-soluble inactive differently leaving para-methylphenyl untouched. Even if you're specifically referring to drugs based on phenethylamine-core like p-methylamphetamine, DOM, 2C-D, or mephedrone, I still can't see the connection between high potency and p-methyl substitution.
 
I agree, the metabolite in question (either 4-carboxy-2c-H or 4-formyl-2c-H) is not active as far as i know.
 
You must log in or register to reply here.
Top