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

  • N&PD Moderators: Skorpio

Question about metabolism of nbome compounds

ebola?

ebola?

Bluelight Crew
Joined
Sep 21, 2001
Messages
22,070
Location
in weaponized form
I have been puzzling this over casually yet am in severe want of knowledge to get to the bottom of the matter. So we all know that the 25x-nbome compounds are essentially orally inactive, possibly even at dosages similar to the parent 2c compound (one user here has trialed to near these types of dosages on himself with careful titration upward. . .sparse, but a datum). I have also further heard that the low pH environment of stomach acid is likely insufficient to explain how these compounds are attacked metabolically (as they are resilient enough to survive such). So this suggests that significant hepatic metabolism by CYP species is very likely. Looking to the metabolism of 2C-B (which is well documented), deamination and subsequent demethylation producing a variety of compounds occurs (Carmo et al. 2005). However, would the 25x-nbomes' novel n-substitution preclude this angle of metabolic attack? Why or why not? What products should we expect to result from hepatic metabolism regardless? I'm wondering whether anything corroborates or suggests incorrect my largely baseless gut-intuition that metabolic cleavage yielding the parent 2C-x compound is possible.

ebola
 
I would assume that it would only offer an additional points of metabolism. It's not all that different from the other end of the molecule, after all.

I know 4-hydroxylation is a major route of metabolism of 4 unsubstituted amphetamines. I assume the same is true of similar benzylamines.
 
sekio said:
Given that we see extensive, presumably CYP-mediated (induced by e.g. phenobarbital) debenzylation of compounds like benzphetamine (N-benzylmethamphetamine), would it not be unreasonable to assume this same pathway could convert NBOMes to their parent phenethylamines?


http://www.ncbi.nlm.nih.gov/pubmed/6624139
Click to expand...


I really don't know, but if they're turning into the parent phenethylamine in the gut, then they should be orally active at roughly the same doses as the parent compound.
 
Given that maybe ~40% of a dose of benzphetamine is N-debenzylated, I'm thinking you may need a pretty serious dose of the NBOMe orally before you see effects.
 
Right, and then you have the inactive molecular weight added by the n-benzyl-2-methoxy substitution, and then you have the built in 'time release' conferred by the nbome compound acting as a prodrug. To my knowledge, the nbome compounds have only been trialed up to oral doses of ~30 mg. Hell, I'd be a little scared at that point: what if residue of the compound gets inadvertently applied to mucosal tissue, and you overdose?

ebola
 
Given that maybe ~40% of a dose of benzphetamine is N-debenzylated, I'm thinking you may need a pretty serious dose of the NBOMe orally before you see effects.
Click to expand...

Actually, wait a minute: wouldn't this level of catabolism be insufficient to explain oral inactivity? So I guess we'd then need to point to the activity of multiple catabolic CYP enzymes. . .

ebola
 
I don't understand. Sekio says that maybe 40% of benzphetamine is N-debenzylated (other metabolism routes involve 4-hydroxylation which is not possible with 25X-NBOMe), so this suggests that N-debenzylation is incomplete with first-pass metabolism in which case some NBOMe arrives in the brain intact. If that is true why is it not active at that point? Do you mean that about half of your dose would be converted to the parent 2C-X (half should still be mildly active though) and the other half would make it to the brain but would take such a long onset period that tachyphylactic effects make you tolerant before you can ever get effects (I take it that is what you mean by the pro-drug action)?

It still doesn't seem like a sound theory, if partial debenzylation is the problem then you should still see effect, it should be one of those cases or somewhere in between...

Or does the tachyphylaxis make you cross-tolerant to effects of the parent 2C-X as well?

What about N-dephenethylation (if I got that right), could that be an explanation? I am not sure what is favored...
 
Solipsis said:
I don't understand. Sekio says that maybe 40% of benzphetamine is N-debenzylated (other metabolism routes involve 4-hydroxylation which is not possible with 25X-NBOMe), so this suggests that N-debenzylation is incomplete with first-pass metabolism in which case some NBOMe arrives in the brain intact. If that is true why is it not active at that point?
Click to expand...

Right. This is what I'm wondering. This mechanism alone can't really explain the oral inactivity. . .so I'm wondering what other likely metabolic routes there are.

Or does the tachyphylaxis make you cross-tolerant to effects of the parent 2C-X as well?
Click to expand...

I don't think that this would make much sense, as it's not clear that there would be significant 5ht2a agonism to elicit tachyphylaxis in the absence of psychedelic effects.

ebola
 
The 2C-Xs are primarily metabolized by MAO-A and MAO-B, not CYP. The major metabolite is the corresponding phenylacetic acid after oxidation of the aldehyde. See the paper here: http://www.ncbi.nlm.nih.gov/pubmed/17067556. MAO has a strong preference for reaction with phenethylamine over benzylamine, about 25-fold higher activity. Thus, it is likely that NBOMes are preferentially metabolized by oxidation of the phenethylamine side rather than the benzylamine.
 
ebola? said:
Good, relevant research right there! But would the 25x-nbome compounds be amenable to attack by MAO?

ebola
Click to expand...

That has not been shown. However, MAOs certainly can react with secondary and tertiary amines (e.g., DMT).
 
Why should MAO's preference of phenethylamines over benzylamines determine which one of those two substrates is more available? I don't know what enzyme would cleave the PEA-NBOMe amine buth I would expect the exact way the substrate binds and is catalytically converts it to determine the more preferred route...
 
Solipsis said:
Why should MAO's preference of phenethylamines over benzylamines determine which one of those two substrates is more available? I don't know what enzyme would cleave the PEA-NBOMe amine buth I would expect the exact way the substrate binds and is catalytically converts it to determine the more preferred route...
Click to expand...

Exactly. Since the NBOMes contain both a phenethylamine and a benzylamine fragment, and the phenethylamine is the preferred substrate, they will bind in the orientation that favors reaction of the phenethylamine. I have done docking of an NBOMe to the structure of MAO-A, and the lowest energy pose is the one with the phenethylamine fragment in the reactive position.
 
Forgive my ignorance, but won't this entail simultaneous cleavage of the benzylmethoxy group and deamination of the resulting phenethylamine compound? Wouldn't this drastically reduce metabolism of 25x-nbome compounds to the parent 2cx?

ebola
 
I think what tryp2fun's data suggests is that there is a lot more metabolism happening from the PEA's perspective than from the NBOMe's perspective because they fit and bind differently on the MAO enzyme active site. Deamination from that PEAA perspective would yield the alhedyde of the PEA and the amine initially stays on the NBOMe i.e. the loose benzylamine before it is also deaminated from that at a lower rate in a later metabolic reaction. There is no simultaneous IMO, I really doubt that the enzyme can catalyze a double deamination all in one go. Ebola I am not sure what you are suggesting 'reduces' any metabolic step but the route to the parent PEA would just not be favored.
But even if you can dock it computationally I am not sure if MAO is able to do this deamination with such a bulky secondary amine substitution, or even if it is responsible for this deamination itself.

If tryp is correct, it would explain it though .. since during first-pass not only is most metabolized before sufficient levels can be reached but it is also mostly turned into products other than the parent PEA, so no action at all.
 
Deamination from that PEAA perspective would yield the alhedyde of the PEA and the amine initially stays on the NBOMe i.e. the loose benzylamine before it is also deaminated from that at a lower rate in a later metabolic reaction. There is no simultaneous IMO, I really doubt that the enzyme can catalyze a double deamination all in one go.
Click to expand...

Quite useful descriptions; thanks!

Ebola I am not sure what you are suggesting 'reduces' any metabolic step but the route to the parent PEA would just not be favored.
Click to expand...

This is a more precise formulation of what I was trying to get at.

ebola
 
4 hydroxylation is absolutely a possibility with these compounds, g though from the benzyl side.
 
Hahah...I don't think that we have any idea about the implications of available SAR, except that the hydroxyl group will reduce BBB penetration.

ebola
 
Last edited:
I think that one shouldn't put too much weight on Benzphetamine as a model for determining the metabolism of the PEA-NBOMe compounds, considering that the a-Methyl substituent greatly affects the metabolization of such compounds. Forgive me if I'm incorrect, but I just notice lots of comparison to Benzphetamine when discussing the NBOMe series of compounds, and considering how metabolism (specifically by MAO) of PEAs (compare PEA to Amphetamine) is greatly affected by the a-Methyl substituent, isn't it a little misguided to put so much weight on the Benzphetamine model?
 
You must log in or register to reply here.
Top