Radaxafine (substituted phenmetrazine)

[Reminisant B]

Just browsing wikipedia and came across a drug called radaxafine which is apparatenly a potent metabolite of bupropion/wellbutrin/zyban.

Turns out its a substituted phenmetrazine.

Do you think the same metabolism may occur in say Ethylone? (as shown in the diagrams below)

 

[nuke]

High NE:DA affinity ratio, do not want, at least for me

It probably occurs, but to a lesser extent.

Oh yeah, ??? is 3-methyl-2-(3,4-methylenedioxy)-phenylmorpholine (MDPM, methylenedioxy-phenmetrazine), and is suspected to have MDA-like effects, but I doubt the concentration after a dose of ethylone would approach what would be needed for it to be active. Unfortunately, it's a little more difficult to make than phenmetrazine itself because the methylenedioxy group prohibits the reductive cyclization in an acidic environment.

 

[Reminisant B]

"Bupropion has also been shown to act as a competitive α3β4 nicotinic antagonist; the α3β4-antagonism has been shown to interrupt certain addictions in studies of other drugs such as ibogaine. This α3β4-antagonism correlates quite well with the observed effect of interrupting addiction." Wikipedia 2007

Just reading the above made me think, as MDPV is so reinforcing would agonism (rather than antagonism with zyban) at the alpha3beta4 nicotinic receptor be an explanation? (or possibly it doesn't work that way) Thought just came to me as the structures aren't that different - as though one could be an agonist and one antagonist.

 

[Riemann Zeta]

I have wondered about some of these substituted phenmetrazines before. I had these compounds listed in a journal as 'putative novel stimulants.' I have no idea as to the activity of these compounds, as the SAR of the phenmetrazines has not been worked out insofar as I know.

And as for the reinforcing properties of MDPV... I never found it to be reinforcing--in fact, even a slightly higher than therapeutic dose was annoying as hell (causing headache and sympathomimetic symptoms). It also seemed as though the half-life of the stimulant effects was shorter than the half-life of the annoying sides. For me, MPDV was almost exactly like methylphenidate (a quick, sweaty ride that just lets you down in the end), but with more headache and a greater PNS stimulant effect. Nothing like the always dependable ultra-suede smoothness of d-amphetamine. The original classic is still the best.

 

[fastandbulbous]

I have no idea as to the activity of these compounds, as the SAR of the phenmetrazines has not been worked out insofar as I know.

My teeny-weenie contribution regarding anorectic activity (which generally corresponds to stimulant properties except for large/unusual reuptake inhibitors) of phenmetrazine derivatives (in rats anyway)

2-phenyl-3-methylmorpholine (phenmetrazine)

good anorectic agent, good cns stimulant. (app more euphoric then amphetamine by injection)

2-phenyl-3,4-dimethylmorpholine (phendimetrazine)

reasonable anorectic. Partially metabolized to phenmetrazine

2-phenyl-3,5-dimethylmorpholine

rather poor anorectic. Possibly steric hinderence at active site of phenmetrazine about heterocyclic nitrogen atom

2-phenyl-3,6-dimethylmorpholine

good anorectic. not much less active than parent molecule (phenmetrazine)

2-phenyl-3-methylmorpholin-6-one

Reasonable anorectic. Short half life compared with phenmetrazine

 

[Jabberwocky]

The methylenedioxy version has not been synthed yet? Why not? Its hard synth but doesn't it sounds promising?

 

[Reminisant B]

2-phenyl-3-methylmorpholin-6-one

Just seen the structure of this one, looks interesting. Was it available as a commercial drug ? Or just as a chemical?



If chlorine substitution works for zyban and its phenmetrizinic (that is indeed a word ) metabolite then the methylenedioxy analogue might have some interesting effects? (To hazard a guess)

 

[Riemann Zeta]

I can see where the keto derivative of phenmetrazine would be active (seems akin to the pemoline / aminorex / 4-MAX series), but extremely short-acting (like methylphenidate), as the lactone could be so easily hydrolyzed.

 

[Reminisant B]

Was just thinking it reminded me of pemoline (sort of). ^

Anyone know if the follwing chemical would be possible? Kind of a phenmetrazine in the style of aminorex.

 

[mysticmusic]

Considering how much more euphoric phenmetrazine is than amphetamine or methamphetamine albeit less potent by weight, adding the 3,4 methylenedioxy to the benzene ring would almost certainly have desirable effects. I would be very interested in all the related subsitutions that are hallucinagenic when added to the amphetamine backbone as well. Although the chemistry may present difficulties the possibilities would likely be well worth investigating.
If anyone tackles any of these I'd love to hear about it!

 

[mysticmusic]

For the record, the added 4-methyl on the morpholine substantially diminished the strength and euphoria of the molecule; phendimetrazine sucks compared to phenmetrazine. At least for me it did. Subsitutions on the phenyl are another matter entirely though.

 

[Hammilton]

Unfortunately it doesn't work like that. A methylenedioxy may make it more potent like mdpv over plain pv, however, it's not going to make it MDMA like. It would have to bind to the right receptors in the right way and given the super tight SAR for MDMA type drugs, I doubt it'll transfer over. With limited prospect for success and complicated and expensive synth, there hasn't been much interest in it. Were there a higher probability of awesomeness someone would have pursued it already. Still, it should be made and tested just for the useful data point but I wouldn't spend the money to do so.

One of those Kiwi companies should, they've got a legal framework to make money off of it if it was good.

 

[atara]

Do you think the same metabolism may occur in say Ethylone? (as shown in the diagrams below)

As Radafaxine is not an ether but a hemiketal, the diagram given misses an OH attached to the benzylic carbon. However this metabolic pathway competes with N-de-ethylation; in the case of an N-tert-butyl substituent it may be favored, but with ethylone the picture is not so clear. It's interesting, though.

 

[mad_scientist]

One of those Kiwi companies should, they've got a legal framework to make money off of it if it was good.

Yeah except that any simple derivative of phenmetrazine will be "substantially similar" to a controlled drug and therefore not allowed to be researched as a novel psychoactive!

For what its worth the SAR data for phenmetrazine in the patent literature suggests that the only really promising substitution on the phenyl ring is 3-fluoro, pretty much every other derivative they tried was substantially less active than phenmetrazine itself (though they didn't try 3,4-methylenedioxy iirc), but 3-fluorophenmetrazine retains similar monoamine release ratios to phenmetrazine with slightly higher potency. The 3-chloro derivative appears to be a selective serotonin releaser, but these have so far generally failed to live up to expectations as novel empathogens...

 

[dingophone]

Wow, are people actually considering radafaxine and it's ilk the future of legal stimulants? Trust me when I say you can guarantee that this drug will be even less 'fun' than bupropion, which already causes nosebleeds, headaches, and even seizures when abused! Same goes for manifaxine.

 

[atara]

Trust me when I say you can guarantee that this drug will be even less 'fun' than bupropion, which already causes nosebleeds, headaches, and even seizures when abused! Same goes for manifaxine.

I'd be interested to hear how you know this. For the most part this is just a thread to speculate about what it might do: the goal of NPD is very much not to support the RC industry!

 

[ebola?]

Yeah except that any simple derivative of phenmetrazine will be "substantially similar" to a controlled drug and therefore not allowed to be researched as a novel psychoactive!

But the CSA has been applied only sparingly and often fails to establish prohibition, depending on the judge's whims, hence the lengthy string of 'emergency' scheduling.
...
BTW, your post is precisely what we need around here. Good to see you popping in.

ebola

 

[ralf2]

For what its worth the SAR data for phenmetrazine in the patent literature suggests that the only really promising substitution on the phenyl ring is 3-fluoro, pretty much every other derivative they tried was substantially less active than phenmetrazine itself (though they didn't try 3,4-methylenedioxy iirc), but 3-fluorophenmetrazine retains similar monoamine release ratios to phenmetrazine with slightly higher potency. The 3-chloro derivative appears to be a selective serotonin releaser, but these have so far generally failed to live up to expectations as novel empathogens...

Would you mind telling where you found this data? I always like to read the original information!

 

[mad_scientist]

Wo 2011/146850....now that I look again it was the other isomer with 3-chlorophenyl that was 5HT selective, my mistake. But yep 3-fluorophenmetrazine is the one that looks most promising, PAL-593

 

[fastandbulbous]

Hello ladies & germs!

Seeing 3'-FPM has reared it's head, I wouldn't be surprised to find some enterprising young thing thinking,"hey what about 3'-fluoro-4-MAR?". Now that's not too daft an idea: 4'-methyl-4-MAR was such a bad idea because 4/para substitutions into phenethylamines inevitably increases serotonogic activity (eg Mephedrone, 4-fluoroamphetamine); basically the last thing you want in aminorex based compounds (5HT2B agonism - pulmonary hypertension etc).
Now 3-fluoronation increases dopaminergic/noradrenergic activity while not touching serotonogic activity or actually reducing it (has to do with the para position in phenethylamines being analogous tothe 5-OH group in serotonin). So 3'-fluoro-4-MAR and/or 3'-fluoroaminorex is a step in the right direction; decreasing serotonic activity while increasing catecholergic activity.
As the above and 3'-FPM share precursors most of the way, I'd say "watch this space".
Over & out, but don't get comfortable, I may be back when you least expect it (cue mad cackle!)