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What does MAOB metabolize PEA to?

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LuxEtVeritas

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Curious as I am not sure what is the metabolic fate of PEA via MAOB and obviously the effect alpha-methylation has on impeding this amongst the other effects it confers

TIA
 
Found this from a research paper:

"The results suggest that the biogenic amine phenethylamine is efficiently sequentially N-oxygenated in the presence of human liver microsomes or cDNA-expressed FMO (form 3) to phenethyl hydroxylamine and then to oximes that are pharmacologically inactive and serve to terminate biological activity. N-Oxygenation of phenethylamine to the corresponding trans-oxime is a detoxication process that abrogates pharmacological activity."
 
Broshious said:
Found this from a research paper:

"The results suggest that the biogenic amine phenethylamine is efficiently sequentially N-oxygenated in the presence of human liver microsomes or cDNA-expressed FMO (form 3) to phenethyl hydroxylamine and then to oximes that are pharmacologically inactive and serve to terminate biological activity. N-Oxygenation of phenethylamine to the corresponding trans-oxime is a detoxication process that abrogates pharmacological activity."
Click to expand...

yes i saw this, but i was unclear if this is via MAOB and if MAOB as i had thought i understood it is the dominant pathway of PEA degradation/deactivation

apparently though this is the path for MAOB (oxidation) as well and what I am curious is to how the alpha-methyl group counteracts this to such a degree and would a "bulky" group on the amine like an N-phenyl group hold any similar effect
 
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also to note apparently AMPH and METH are also susuceptible to this pathway of degradation alluded to in the above study cited by Broshius that was in regards to PEA

Vol. 288, Issue 3, 1251-1260, March 1999


N-Oxygenation of Amphetamine and Methamphetamine by the Human Flavin-Containing Monooxygenase (Form 3): Role in Bioactivation and Detoxication1
John R. Cashman2 , Yeng N. Xiong, Lifen Xu and Aaron Janowsky2

Human BioMolecular Research Institute, San Diego, California (J.R.C., Y.N.X., L.X.)

(+)- And ()-amphetamine and methamphetamine were N-oxygenated by the cDNA expressed adult human flavin-containing monooxygenase form 3 (FMO3), their corresponding hydroxylamines. Two major polymorphic forms of human FMO3 were studied, and the results suggested preferential N-oxygenation by only one of the two enzymes. Chemically synthesized (±)-amphetamine hydroxylamine was also a substrate for the human FMO3 and it was converted to phenylpropanone oxime with a stereoselectivity ratio of trans/cis of 5:1. Human FMO3 also N-oxygenated methamphetamine to produce methamphetamine hydroxylamine. Methamphetamine hydroxylamine was also N-oxygenated by human FMO3, and the ultimate product observed was phenylpropanone. For amphetamine hydroxylamine, studies of the biochemical mechanism of product formation were consistent with the production of an N,N-dioxygenated intermediate that lead to phenylpropanone oxime. This was supported by the observation that -deutero (±)-amphetamine hydroxylamine gave an inverse kinetic isotope effect on product formation in the presence of human FMO3. For methamphetamine, the data were consistent with a mechanism of human FMO3-mediated N,N-dioxygenation but the immediate product, a nitrone, rapidly hydrolyzed to phenylpropanone. The pharmacological activity of amphetamine hydroxylamine, phenylpropanone oxime, and methamphetamine hydroxylamine were examined for effects at the human dopamine, serotonin, and norepinephrine transporters. Amphetamine hydroxylamine and methamphetamine hydroxylamine were apparent substrates for the human biogenic amine transporters but phenylpropanone oxime was not. Presumably, phenylpropanone oxime or nitrone formation from amphetamine and methamphetamine, respectively, represents a detoxication process. Because of the potential toxic nature of amphetamine hydroxylamine and methamphetamine hydroxylamine metabolites and the polymorphic nature of N-oxygenation, human FMO3-mediated metabolism of amphetamine or methamphetamine may have clinical consequences.
 
the a-methyl group prevents it from fitting in the enzyme pocket as well, so it cannot be degraded nearly as easily

when you start tacking on large groups, it get harder to cross the BBB/fit in the receptor pockets as well
 
^ depends on the target - extending the chain length of beta keto amphetamines (cathinone derivatives) gives more potent DAT inhibitors. Basically (sweeping generalization time!), the further you get away from the neurotransmitter(s) the enzyme normally targets, the less susceptable it is to metabolism by that enzyme
 
to finish the sweeping generalizations, the further you get from the structure of the neurotransmitter, the less able the molecule is to fit into the native receptor properly as well.

The exceptions are obviously quite numerous though

how long can you go on the keto derivatives before there is no longer an increase/a drop in potency?
 
Can anything work well without the alpha-methyl though is one of the issues i am looking at

such as a PEA that has a somewhat bulky group at the beta and N positions but no alpha-methyl which is thusfar fairly intrinsic to see any real strong effects as in AMPH, EPH, CATH, et al

since the alpha is largely crucial to prevent quick metabolism i was wondring is such other substitutions might impact to prevent metabolism/degradation and maintain a reasonably potent relative stimulant profile
 
the pyrroidine which is i guess the amine portion of MDPV obviously does not obscure receptor binding

hence again wondering where something like a N-phenyl might play in this regard

of course though MDPV has the alpha-"appendage" which serves the same basic function to a large degree i suppose as the alpha-methyl of the more common agents (prevents degradation, et al) , though its bulkiness also serves to create a slant toward preferential DARI effect

the same DARI enhancement will occur to some degree if you "bulk up" the beta- position I believe
 
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