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Benzocyclobutene MDMA analog

wungchow

wungchow

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It's my understanding that a regular benzene ring is not a strict requirement for amphetamine and its analogs to be recognized at the relevant receptors. (i.e. Br-DFly has an extended conjugated ring system yet still maintains psychedelic activity.)

I was wondering if in MDMA, we replace the benzene ring with a benzocyclobutene ring:

Benzocyclobutene_simple_structure.png


with the cyclobutene moiety extending from the 5,6 positions. and the MD group at its normal 3,4 position. it seems like this molecule would have identical effects to MDMA. but who knows?
 
Except that MDMA does not act principally at postsynaptic 5HT receptors but rather on the presynaptic monoamine transporters. Binding at these sites may be governed by different rules about conformation.
 
Well the (R)- cyclobutane deriv's (but with 2,5-diMeO substituents on the benzene ring) are 5-HT2A agonists of very high affinity.
Obviously the alkene will alter the spatial orientation of the sidechain - would be interested to see what effect this has for the affinity to monoamine reuptake transporters. The cyclobutene part may introduce too much hindrance for it to bind well. 5-HT2A agonists and monoamine reuptake inhibitors+releasers have different SAR requirements and so the structures may be incompatible!
 
i still think that the amount of hindrance introduced by the cyclobutene ring would be fairly small, allowing the molecule to bind in a very similar fashion
 
quick couple of thoughts.

I think you will probably find that the cyclobutene is rather less stable in vivo than the benzocyclobutane.
IIRC benzocyclobutene requires an electron withdrawing group to retain stability, otherwise it is very prone to photolytic cleavage and also participating in diels alder type additions.

the butene will hold the side chain flat to the alpha sidechain position wheras the butane will force the side chain out of plane at the alpha position, the bioactive configuaration of amphetamine is with the side chain out of the benzene ring plane, probably true for the releasing properties of MDMA too. but who knows.

also are you proposing an 2-methyamino ethyl chain at the 1 position of the butene ring or a methylamino methyl?

tricky chemistry. and very similar flattening of the side chain can be done using a couple of other much easier modifications for example adding a methylene group at the benzylic position of MDMA
 
actually i wasn't proposing that the sidechain be attatched to the cyclobutane moiety. it would be at its normal position. the cyclobutane ring would be fused to the 5 and 6 positions on the benzene ring, basically just creating a slightly bigger aromatic system
 
would it look like this?
4lqh1lw.gif

I really dont know much about structure activity relationship and all that, but from reading pihkal is seems that even subtle changes often have a significant effect on activity. But who knows really. Any reason to believe this would be a superior compound.
 
wungchow said:
actually i wasn't proposing that the sidechain be attatched to the cyclobutane moiety. it would be at its normal position. the cyclobutane ring would be fused to the 5 and 6 positions on the benzene ring, basically just creating a slightly bigger aromatic system
Click to expand...

my apologies I hadn't realised you proposed to leave the sidechain where it is.
now that looks even more of a bitch to synth than the first one :(
its all wrong with respect to possible precursors.

there is of course the cycloheptyltriene system which is fairly stable it is found in some natural products if all you want is a bigger aromatic system.
 
This thread mentioned aminomethylbenzocyclobutenes.

As for synthesis; the link to the paper on the above thread isn't working, but the paper should be available from someone around here. As well, I have a book that has a section that outlines synthetic approaches for these substances

The chemistry of cyclobutanes
Edited by Z. Rappoport and J. F. Liebman, 2005 John Wiley & Sons, Ltd. ISBN: 0-470-86400-1
 
as mentioned, that cyclobutene ring is aching for a diels-alder rxn or something to alkylate to open up that chain.
probably not a good candidate for eating
as far as the pharmacology, has there even been a good reason for this proposed? does the good dr even make a 5,6 methyl compound? probably not, as even the 2,5 dimeo 3,4 dimethyls are stupidly hard to make.
like vecktor said, extending the chain from the cycolobutene opens up more posibilities and nichols has done this with the PEAs with good results
 
Oh, right? I hadn't even considered that you didn't want to put the sidechain off thr the cyclobutene ring. Why in hell would you want that ring hanging off the benzene ring? What makes you think it'd be any good?
kidamnesiac: Yes it's true Nichols had luck doing that but that was for 5-HT2A agonists, not monoamine reuptake inhibitors/releasers, as said before :) .
 
the goal would be to make a compound with the same level activity, but it circumvents the ban on regular MDMA
 
actually now i wonder what would happen if you took MDMA but replaced the 3,4-MD with the cyclobutene ring. seems like you would get effects similar to indanylamphetamine
 
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