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Hhma

Dresden

Dresden

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Joined
Feb 2, 2010
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3,212
How bad is this one for you, honestly? More, less, or equally damaging as MDMA? Will it get you high? Or, as I suspect, do the true answers to these questions lie somewhere along the lines of so few people if any have ever done HHMA that we don't and mayn't ever have a flippin' clue?

1-(3,4-dihydroxyphenyl)-2-methylaminopropane.png


HHMA
 
It won't get you high. The logP is too low, won't cross the blood brain barrier.

When it's generated in the brain through MDMA metabolism it is supposed to be a neurotoxic chemical that damages through redox cycling.
 
Phenols and catechol metabolites of MDMA/MDA seem to play a significant role in these compounds neurotoxicity. It's a shame because active amphetamines derived from formyl-veratrole and a vanillin would be a very nice thing.

Does anyone know what effect ethers other than methyl might play in terms of metabolism? Would bulkier alkyl substituents be more or less prone to dealkylation?
 
Sekio, what enzyme metabolises that in the brain? Anyhow, that is the only way it'd get into the brain in large enough quantities. If N,alpha-dimethyldopamine was a metabolic product of the liver, it would be way too polar to cross the BBB.
 
Dresden, your second compound would probably get into the brain fine; phenol logP itself is 1.3-1.7 so the alkyl chain should push it above 2. My question is why? What is the rationale of the phenolic groups.
 
I lifted the 3-pentylphenol from

3-(4-pentyl-2-hydroxyphenyl)-cyclohexanol.png


the CP-xx,xxx cannabinoid and combined it with the amphetamine structure instead of the cyclohexanol one.
 
aced126 said:
Sekio, what enzyme metabolises that in the brain? Anyhow, that is the only way it'd get into the brain in large enough quantities. If N,alpha-dimethyldopamine was a metabolic product of the liver, it would be way too polar to cross the BBB.
Click to expand...

CYP2D6 and other CYP's i think. HHMA has allegedly been identified in the rat brain after subcutaneous administration of MDMA at least (http://jpet.aspetjournals.org/content/313/1/422.short).
 
Woah, why are these enzymes in the brain at all. Especially metabolic CYP enzymes, which primarily metabolise xenobiotic compounds into more polar metabolites. I don't see any biological usefulness for them being in the brain. Enzymes don't metabolise compounds "because they are toxic". They metabolise them because they are exogenous and thus have a chance of being toxic, and they don't necessarily convert them into a non toxic metabolite; they convert them into a more polar metabolite.

If CYPs were in the brain they'd be making drugs more polar metabolites within the brain and thus delaying excretion; the polar molecules would be trapped in the brain because they can't cross the BBB. If anything this is going to lead to increased toxicity of many compounds. If someone with more biological knowledge than me could suggest why these enzymes exist at all in the brain that would be appreciated.
 
Yeah of course the metabolism isn't always just good, there are plenty of examples where it actually gets worse when some molecule takes the wrong metabolic pathway ... but I'm really curious about the question too!
 
I've never seen a metabolic reaction where the metabolite which is intended to be excreted has become less polar.
 
aced126 said:
Woah, why are these enzymes in the brain at all. Especially metabolic CYP enzymes, which primarily metabolise xenobiotic compounds into more polar metabolites. I don't see any biological usefulness for them being in the brain. Enzymes don't metabolise compounds "because they are toxic". They metabolise them because they are exogenous and thus have a chance of being toxic, and they don't necessarily convert them into a non toxic metabolite; they convert them into a more polar metabolite.

If CYPs were in the brain they'd be making drugs more polar metabolites within the brain and thus delaying excretion; the polar molecules would be trapped in the brain because they can't cross the BBB. If anything this is going to lead to increased toxicity of many compounds. If someone with more biological knowledge than me could suggest why these enzymes exist at all in the brain that would be appreciated.
Click to expand...

They don't just exist to metabolize xenobiotic compounds. CYP450 enzymes are required for synthesis and degredation of cholesterol and steroids, and other biochemicals. Eg. CYP7B synthesizes neurosteroids.
 
What is the role of CYP2D6 in the brain? It definitely isn't to metabolise xenobiotic compounds; that's just chance
 
aced126 said:
What is the role of CYP2D6 in the brain? It definitely isn't to metabolise xenobiotic compounds; that's just chance
Click to expand...

As I wrote above, CYP450 enzymes are required for the biosynthesis (and degredation) of biochemicals such as steroids and fats. Neurosteroids are synthesized by CYP7B.
 
Sorry, I should have been more specific in my question: what particular steroid and fat synthesis is catalysed by 2D6?
 
Anandamide, endorphins, progesterone, tryptamine, tyramine, etc, may be endogenous substrates.
 
check this out

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1573171/

catechol metabolites of MDMA (3,4-dihydroxy and 3-OH-4-MeO amphetamine and N-methyl homologues) caused a raise in vasopressin and oxytocin levels in vitro. although HHMA wasn't really outstanding in doing so, HHA (referred as DHA in the article) and HMMA (3-OH-4-MeO) were more effective in evoking this release than MDMA.

anyone know what would be the mechanism behind this release?
 
The metabolite isn't intend to be excreted because it isn't a xenobiotic compound. That compound, dopamine, is endogenous and so there is a wholly different regulatory system for that and like neurotransmitters.
 
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