Mdfa

[jackson2004]

Would methylenedioxy fluoroamphetamine be potentially active compound, and if so, would someone care to stipulate as to effect, potency, toxity, etc.

 

[nuke]

This is very vague. Where are you fluorinating the compound? If you fluorinate the carbon by the oxygen then you run the risk of having the fluorinated carbon metabolized off.

 

[MurphyClox]

@Nuke:
Nope, if you fluorinate the methylene-bridge (I assume it was that what you meant), you won't see much metabolisation at that site. The difluoromethylene-congener of MDMA was designed for exactly that reason.
See: Chemistry & Biodiversity 2006, 3, p.326

Fluorinated compounds in general can't be handled by native enzymes (that's just one reason why fluorine is introduced into the metabolic sites in some molecules...it extends the compound's halflife).
Even if it would get metabolized: What is so problematic with a fluoro-substituted C1-structure?

But I agree with the notion, that the original question is quite vague. I can imagine 6 (maybe 7) sites in MDA where one could place a fluorine.

Peace! Murphy

 

[dread]

Why not all of them!

 

[nuke]

@dread
lol

@MurphyClox
That's interesting. Did the authors of the paper actually assess any of these compounds for their ability to produce neurotoxicity?

I'd be kind of willing to bet difluoromethane isn't the best thing for your body... Maybe not intensely toxic but probably not great (would you ever eat any DCM?).

 

[MurphyClox]

@Dread:
Nitrogen-fluorine bonds are not really stable and agents with such bonds are used to introduce fluorine into other compounds. It also doesn't make sense to fluorinate all possible positions, because the electronic state of the compound would get profoundly altered... It's everything but sure that your suggested molecule will be active.
Ahh, and I just noticed that you forgot to fluorinate one position in your substitution-frenzy-mood. (You wrote: "Why not all of them!") Which one could it be?

@Nuke:
Unfortunately, no neurotox data was assessed. The authors pointed at an upcoming publication, but until now nothing was published. I'm really anxious to see further data.

About the DCM/DFM-issue: Fluorine possesses a really unique position among all compounds. One reason is the high electronegativity, paired with its small size. While one can compare the other halogens with each other, I have to stress that fluorine is indeed unique in most of its properties... Lots of organic fluorine compounds are not significantly toxic, because we just don't have any enzymes to handle them.
For exactly this reason, too, lots of organofluorines stay years or even decades in the environment. You also won't find much natural organofluorines, I think the number of known natural (organic!) compounds containing fluorine is below 50. That's nothing!

Peace! Murphy

 

[Limpet_Chicken]

Murph, not having enzymes that can handle them, is actually a reason for some to be toxic.

The interesting organofluorine fluoroacetate is found in an african plant, and its highly toxic, as it gets metabolised to fluorocitrate, which goes on to bugger the krebs cycle.

Highly potent, no antidote, used as rat poison under the name '1080'

Then there are of course the unnatural flurophosphorus cholinesterase inhibitors like sarin, VX and the novichoks which are nasty, really nasty and 'your up shit creek' in that order.

 

[MurphyClox]

Ok, well, I oversimplified a bit. Limpet got a point.

Fluoroacetate inhibits the citrate synthase, 'cause it gets 'confused' by the enzyme for the native substrate which binds it. Then the enzyme stops and so does the citrate cycle. Geeee...

In nerve agents the fluorine is not obligatory, e.g. does VX not have one (and its one of the most potent agents!), as well as Tabun. It's the phophorous (ester) that makes these compounds so drastically toxic.
I admit, there are of course toxic organofluorines. But the presence of a fluorine does not pose toxitity per se!

Peace! Murphy

 

[Limpet_Chicken]

I didn';t mean to imply it did

VX isn't the most toxic of the nerve agents though, newer member of the novichok series, real potent, up to stated 10x the weight toxicity of VX, and they contain an oxime functional group to bugger any attempt to reactivate the poisoned enzyme.

Soman is nasty too, G type agent, less toxic by weight than the V series, novichocks or VG types, it 'ages' the enzyme after binding, and rapidly changes its structure (within ten minutes as opposed to a day or even 40 hours for VX and VR), after which oxime treatment has no effect.

 

[Xaratoostrah]

t's everything but sure that your suggested molecule will be active.
Ahh, and I just noticed that you forgot to fluorinate one position in your substitution-frenzy-mood. (You wrote: "Why not all of them!") Which one could it be?

Sorry for jumping in ,but could it be the carbon directly left from the Nitrogen? It has one bond with the NF2 group, one bond with the CF2 group that binds with the ring, and one bond with the CF3 group (where the "meth" of 3,4 methylenedioxyMETHamphetamine would be). So one bond missing ,or more correctly still having its hydrogen not replaced with fluorine.

The authors pointed at an upcoming publication, but until now nothing was published. I'm really anxious to see further data.

Well ,count me in. It looks...quite promising in my eyes if it has LESS neurotoxity ,but the magnitude of effects are on the same scale as the parent compound. A "safer MDMA" to oversimplify? Propably, if the neurotoxic effects are solely attributed to the methylenedioxy bridge. Still,if we take the "dopamine hypothesis" (it hasnt been disapproven ,has it?) it would be realistic to talk about less toxicity, not complete absence of it -that said in order not to give the wrong impression to most members hastily reading the thread!-

 

[dread]

Murphy, it's called a joke... and yeah, I just noticed. The alpha-carbon is missing a fluorine! I feel so ashamed now...

 

[MurphyClox]

Sorry for jumping in ,but could it be the carbon directly left from the Nitrogen?

Yep!

A "safer MDMA" to oversimplify?

Exactly! And I also agree with you that "safer" does not imply "completely safe", as MDMA's neurotoxicity has several causes, the 3,4-dihydroxy metabolite just being one of them.

Murphy, it's called a joke...

And I understood it as such...

Peace! Murphy