toxic sulfur metabolite in Methiopropamine?

[fridgebuzz]

Don't usually see many sulfurs in drugs. Once this molecule begins breaking down inside the body, what becomes of it?

 

[sekio]

Probably:

Thiophenylacetone will be nasty, I guarantee it.

I don't see anything else obvious, maybe ring opening or epoxidation. I'm not an expert on metabolism. And even M1 (1-(thiophen-2-yl)propan-2-amine) is absent from the literature. "Research Chemicals"...

 

[fridgebuzz]

Sekio, could you link me to any good reading on drug metabolism? Sorry if this is the wrong place. I'm intensely interested in toxic metabolites after seeing this sulfur, and a fluorine appear in another substance.

 

[sekio]

My advice; learn organic chemistry and study the metabolic pathways of comparable drugs. Eventually you can extrapolate metabolism pathways based on certain structural features.
Reading the literature helps a lot too.

The mere presence of sulfur or fluorine is not damning in a chemical compound. What's bad in general are things that are toxic because of their reactive nature or things that are toxic because of their negative interaction with bodily functions. For instance 4-MTA is considered "bad" not because of the sulfur but because it is both a powerful monoamine releaser and a MAOI. Another example is why the 2c-* series with halogens in them are not "toxic" the same way the 4-haloamphetamines are - the amphetamines are strong monoamine releasers and the 2c's are not.

If you are concerned about simple aromatic fluorination, e.g. 4-fluoroamphetamine, generally those substitutions will block metabolism at best. The only practical way you can release the fluorine off the ring is with fire.

 

[Molecular_Man]

What's the final verdict on that "possible" route?

 

[T. Calderone]

Bdd ----- > npd

 

[DrGreenthumb]

The main metabolite detected in urine in the N-demethylated metabolite nor-MPA,

showing that methiopropamine is only metabolized to a minor extent. The metabolism

includes the cytochrome P450 enzyme CYP2C19 in the liver. In in vitro studies, traces

of methiopropamine hydroxy metabolites could also be detected. However, these

metabolites could not be identified in human urine [11-14].

source: http://www.who.int/medicines/areas/quality_safety/4_23_review.pdf (pdf)

 

[s0rsha]

I am assuming that you are not a rat so here's a nice overview of the pathway with the rat-only metabolites grayed out and the names for the relevant metabolites listed (adapted from this paper, in which Bluelight also happens to be mentioned):

 

[endotropic]

So 3G, 4G and 5S shouldn't occur at all in humans, considering the intermediates can't form? That fits with what Drgreenthumb posted about metabolite detection in human urine.

 

[s0rsha]

As for phase I metabolites (identified through GC-MS), indeed, only the parent compound and the nor-metabolite were detected in the human urine sample. The phase II metabolites hydroxy-alkyl glucuronide, nor-hydroxy-alkyl glucuronide and hydroxy-aryl sulfate were detected in human urine through LC-HRMS (and also in rats, hence the R/H). Thus the rat-specific intermediates seem to suggest metabolic differences between species (or they were unable to detect these in the human sample for whatever reason, given that hydroxyl groups tend to serve as sites for glucuronidation and sulfation). All things considered the drug is indeed mostly excreted unchanged with some nor-2-MPA for good measure.

 

[sekio]

Is thiophenylacetone not detected at all?

 

[s0rsha]

Each and every compound found in human and/or rat urine is in the figure previously posted so it would seem like thiophenylacetone is absent. Even nor-2-MPA is not formed to a very big extent...

 

[Molecular_Man]

Thanks guys.. This is good news!

 

[adder]

So 3G, 4G and 5S shouldn't occur at all in humans, considering the intermediates can't form? That fits with what Drgreenthumb posted about metabolite detection in human urine.

If they could form, then why would no beta-O-glucuronides of ephedrine be detected in urine? I was interested in this while considering how beta-ketone in bk-2C-B affects its effects and what makes it last so long and I couldn't find a single article confirming that ephedrine is metabolised through glucuronidation of beta-hydroxy. On the other hand, if ephedrine can be p-hydroxylated and then conjugated, why wouldn't MPA be hydroxylated at the aromatic ring and then conjugated?