MDMA like compound

[djsim]

Hey all, I know his is highly hypothetical... but here goes.
Anyway, I just finished doing a review on MDMA for one of my uni classes. I had to draw up a bunch thing like MDMA, MDA, MMDA (MDMA with methoxy at 5 position)... anyway, I fell asleep while drawing and kinda dreamed about what i was doing when i fell asleep.
Is this compound possible?
[attachment]

Curiosity just got the better of me. I know it would be very hard to find a precursor with those substitutions on the benzene, but yeh, is it possible? Would you expect it to have activity? The strain would be pretty great though, yeh?
Your thoughts appreciated

 

[MurphyClox]

Synthesis is indeed problematic, if not impossible. Look at the strain inflicted in this energy minimized model:


I: view from above
II: view in direction of the arrow. Please note how the benzen-ring gets slightly twisted!

Then again: What for? 'cause I wouldn't expect significant activity, especially not like MDMA. The steric bulk of the additional -OCH2- would disrupt receptor affinity IMO. Compare for example MDMC (PIHKAL #110). Quoting Shulgin:

What a strange and completely unsatisfactory compound!

(he comments not only about potency but also quality of the compound)

Peace! Murphy

 

[dread]

How about this one:

 

[MurphyClox]

This one is known, I just don't remember the article right now.

Due the the change from a methylenedioxy-bridge to a difluoromethylen-derivative the compound was less subject to metabolism (at this particular site). Now it was shown that is is indeed the dihydroxy-metabolite that mediates a significant part of MDMA's neurotoxicity rather than MDMA itself. For this reason the compound was proposed to be less neurotoxic.

Anybody got the exact reference at hand? IIRC, there were even bioassays (rats?) employed... I would like to hear if somebody can present own experience. Anybody ever tasted this one?

Peace! Murphy

 

[planckunit]

This one is known, I just don't remember the article right now.

Due the the change from a methylenedioxy-bridge to a difluoromethylen-derivative the compound was less subject to metabolism (at this particular site). Now it was shown that is is indeed the dihydroxy-metabolite that mediates a significant part of MDMA's neurotoxicity rather than MDMA itself. For this reason the compound was proposed to be less neurotoxic.

Anybody got the exact reference at hand? IIRC, there were even bioassays (rats?) employed... I would like to hear if somebody can present own experience. Anybody ever tasted this one?

Peace! Murphy

I don"t have time to look it up right now, but I'm pretty sure it was by Trachsel.

 

[djsim]

Synthesis is indeed problematic, if not impossible. Look at the strain inflicted in this energy minimized model:


I: view from above
II: view in direction of the arrow. Please note how the benzen-ring gets slightly twisted!

Then again: What for? 'cause I wouldn't expect significant activity, especially not like MDMA. The steric bulk of the additional -OCH2- would disrupt receptor affinity IMO. Compare for example MDMC (PIHKAL #110). Quoting Shulgin:

(he comments not only about potency but also quality of the compound)

Peace! Murphy

Thanks Murphy, I thought you might know. I knew the torsional strain would be great, so synthesis would be nigh impossible.
PS. just to clarify, this is a real dream I am talking about. Not a "SWIM" totse-esqu kind of dreamn

 

[djsim]

This one is known, I just don't remember the article right now.

Due the the change from a methylenedioxy-bridge to a difluoromethylen-derivative the compound was less subject to metabolism (at this particular site). Now it was shown that is is indeed the dihydroxy-metabolite that mediates a significant part of MDMA's neurotoxicity rather than MDMA itself. For this reason the compound was proposed to be less neurotoxic.

Anybody got the exact reference at hand? IIRC, there were even bioassays (rats?) employed... I would like to hear if somebody can present own experience. Anybody ever tasted this one?

Peace! Murphy

shit that's intersting... but making it would require difluoromethylen-derivative of MDP2P yes? Cos I know stuff like fenfluramine requires simple hydrogenation of (Trifluoromethyl-3'-phenyl)-1-oximino-2-propane.

 

[MurphyClox]

Fenfluramine contains a trifluoromethyl-group (-CF3), while we're talking here about a difluoromethylene-bridge (-O-CF2-O-). Synthesis is like 'normal' MDMA's, but starting with a OCF2O instead of a OCH2O-substituted starting material. No synth details here...

Murphy

 

[MurphyClox]

Thanks to planckunit, Trachsel is indeed the author if this material.
See Chem Biodivers 2006, 3, p.326.

It's indeed quite insightful:

As the above-mentioned pattern of metabolism (Scheme 1) can occur in all 3,4-methylenedioxy compounds, the question arises whether a blockade of the metabolic pathway in such compounds may, at least partially, prevent neurotoxicity. It has been found that the selective serotonin-reuptake inhibitor (SSRI) fluoxetine, which antagonizes the cleavage of the CH2 bridge of MDMA by inhibiting cytochrome P450 (CYP2D6), prevents the neurotoxicity of MDMA (1b). However, it has been found that MDMA itself seems to inactivate this particular enzyme, and SSRIs would also prevent access of MDMA, neurotransmitters, or metabolites to the serotonin transporter. Thus, it remains questionable through which mechanism neuroprotection occurs.

In this paper, we present the synthesis and characterization of the novel 3,4-(difluoromethylenedioxy) analogues 3 - 5. Their metabolic and toxic effects will be the subject of an upcoming paper.

DAMN! To my knowledge, this upcoming paper wasn't published yet... Or was it?

Peace! Murphy