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    benzoxazole analogs of MDMA 
    #1
    I'm sure this must have been discussed before somewhere on this site, but I can't find it. Is anyone aware of the benzoxazole and benzimidazole analogues of MDMA or MDA having been studied. They have the H bond acceptors in the right place and are approximately the same bulk as the benzodioxole of MDMA. sadly the lipophilicity isn't quite right.
    I have seen work on benzoxazole analogues of tryptamines but not 3,4 amphetamines.

    most interest is the benzoxzole analog
     

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    #2
    Bluelight Crew fastandbulbous's Avatar
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    As the activity is closely linked to the oxygen atom at poition 3 on the ring, it seems to suffer even from slight changes (such as removing the ring constraint to give 3-methoxy-4-methylamphet,), I'd be inclined to think the benzoxazole would be the best bet
     

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    #3
    Bluelight Crew Swerlz's Avatar
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    @fast, i love your knowledge
     

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    #4
    Bluelight Crew fastandbulbous's Avatar
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    Dave Nichols is the impressive one - he did all the research work; by comparison all I have to do is remember it
     

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    #5
    has there ever been a study with the N-homologs @ the 3 position? I would love to see the benzimidazole, I imagine the (having studied imidazoles for a while) that the ring would be much harder to crack open and cause oxidative damage, probably lessening the doses required and increasing the duration of action.
    My physical organic is a bit weak lately, but why would the lone pairs on the Oxygen be any more efficacious than the lone pair on the N?
    I also think the funky pKa of the imidazole would make it a damned interesting pharmacological agent in vitro. Run your receptor test @ pH 8, then pH 6 and see how it changes things. That's a thesis right there!

    ps. Congrats on hitting the magic 10,000 post mark. Your "No Life" award will be in the mail shortly
     

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    #6
    Ex-Bluelighter Helios.'s Avatar
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    Oxygen is necessary for entheogenicity.
    O is aromatic. N is anti-aromatic.

    DOA, eg, is inactive while TMA-2 is active.
     

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    #7
    Why then does the indole system work well?
    It's a sort of hemi-FLY compound (sort of).
     

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    #8
    Ex-Bluelighter Helios.'s Avatar
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    B/c it works on the 5-HT system, whereas the PEAs work on the dopamine circuits.

    Can somebody posts the structures of exactly what he is talking about?
    I can tell you a lot more usually if I see the structure.

    I do recall hearing that the amphetamine (minus its phenyl ring) backbone attached to the 5-indole site yields a stimulant. No idea how to synth that though unless you have 5-carboxaldehyde-indole.

    Ok, nevermind I figured out what he means.
    The benzimidazole (2 N ring, right?) analogue would not be active I think.
    There are 2 benzoxazole analogues possible.
    I would think that the one with the O para to the aliphatic chain would be more active, but I surmise both to be somewhat active.
    Also, the N-methyl versions will be better.
    Last edited by Helios.; 05-02-2007 at 13:51.
     

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    #9
    Ex-Bluelighter Helios.'s Avatar
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    Update
    I am pretty sure that at least on of the two benzoxazole analogues will be active.
    I am quite sure that the N-methyl version is what you'll want as well.
     

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    #10
    I was more nitpicking at your use of "ethenogenicity", and oxygen being required for this. No - oxygen may be required for empathogen behavior (although, not necessarily so), but not for ethenogenic behavior (which includes psychedelics).

    Besides, oxygen isn't required - the oxygens in a methylenedioxy ring can be replaced with CH2's - this results in a selective sertotonin releaser, which sucks compared to MDMA subjectively because the 5-HT to DA & NE ratio is too high.
    Or, IIRC.
     

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    #11
    Quote Originally Posted by Helios.
    Oxygen is necessary for entheogenicity.
    O is aromatic. N is anti-aromatic.

    DOA, eg, is inactive while TMA-2 is active.

    eh? benzimidazole is certainly aromatic, as is the oxazole.

    and comparing a primary amino compound to an ester isn't really fair.

    I've also never seen an info on DOA, could you link some?
     

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    #12
    Bluelight Crew fastandbulbous's Avatar
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    The activity about the substituent on the 3 position is all about the orientation of lone pairs for their interaction with DAT & SERT. A methylenedioxy ring is just the closest to ideal Not sure how much it would suffer by having the two lone pairs if an oxygen replaced by a single lone pair from a nitrogen (I suppose someone could make it and see! ), but replacing the oxygen with a CH2 just leaves it with mostly SERT activity (as with IAP), which isn't enough on it's own
     

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    #13
    Never tried IAP, any good?
     

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    #14
    Bluelight Crew fastandbulbous's Avatar
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    I'd predict most people couldn;t distinguish between MDA and an IAP/amphetamine combo, but on it's own it is definitely lacking (the amphetamine could be any dopaminergic drug, just that was what I had when I had some IAP)

    The combo has everything, including serious time dilation and those fucked up hallucinatory episides, but I think I was about the only one who lamented the disapearance of IAP from the marketplace
     

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    #15
    Quote Originally Posted by fastandbulbous
    The activity about the substituent on the 3 position is all about the orientation of lone pairs for their interaction with DAT & SERT. A methylenedioxy ring is just the closest to ideal Not sure how much it would suffer by having the two lone pairs if an oxygen replaced by a single lone pair from a nitrogen (I suppose someone could make it and see! ), but replacing the oxygen with a CH2 just leaves it with mostly SERT activity (as with IAP), which isn't enough on it's own

    well as far as I can determine a couple of benzoxazolin-4-yl and 5-yl ethylamines have been made and reported but so far cannot find any isopropylamines..
    when I get time I will search CA.
    I am tending to think the only answer will be through the make em taste em approach. The benzoxazole appears to be well tolerated and stable. the theoretical synthesis is looking interesting.
    My hunch is that the lipophilicity of the 1,3 azole moety will be much less than the Methylenedioxy moety and so will give ADME problems.
    On the plus side it will end up stuck in the vesicles if it is taken up by DAT or SERT, and screw with the pH which would bode well for releasing properties.

    I don't have the paper anymore but nichols did investigate the dihydrofuran analog of MDMA I think it was the isomer with the 4 position oxygen replaced with 'Carbob' which fully substituted for the training drug. am i correct in thinking the 4 position o seems less critical for DAT SERT selectivity than the 3 o? If that is the case then that is where the N should go.
     

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    #16
    yea, in some ways it seems the SARs proposed in this thread contradict the entactogen/entheogen ideas.
     

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    #17
    Quote Originally Posted by fastandbulbous
    The activity about the substituent on the 3 position is all about the orientation of lone pairs for their interaction with DAT & SERT. A methylenedioxy ring is just the closest to ideal Not sure how much it would suffer by having the two lone pairs if an oxygen replaced by a single lone pair from a nitrogen (I suppose someone could make it and see! ), but replacing the oxygen with a CH2 just leaves it with mostly SERT activity (as with IAP), which isn't enough on it's own
    Both the imidazole and oxazole would, obviously, be planar moieties as well. With the quadrapole of electronegativity/carbon/electronegativity sandwich presenting itself very similarly to the dioxole.
    Now I'm having a brain fart, but in an oxygen aromatic heterocycle, one lone pair is participating in the aromaticity. what is the other pair doing? sticking straight out with the plane of the molecule ala the trigonal planar conformation adopted by a nitrogen in the same predicament (sp2)? It just seems really strained on what would normally want to be a tetrahedral atom.-a 4th year pHD student seems to agree with me on this one...
    looking it up in my organic book does indeed show the lone pair sticking out with the plane of the aromaticity.
    anyway
    If this is true, than I can't see the difference between having an aromatic nitrogen there and an oxygen. The lone pair on the oxazole is not participating in the aromaticity and the oxygen is behaving as would be expected. IMHO, the oxazole would be almost undistinguishable.
    Looking at it again, the imidazole would certainly be more tricky as only one lone pair is not participating in the aromaticity at any given time although this changes with resonance so it would seem that it would be almost a wild card where you would get both the IAP-like effects and binding to either the 3 or 4 position electron pair seekers (at different times) with the same molecule.

    I'm sure this is most confusing, I'll try to chem draw up some pictures later in the week.
     

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    #18
    Quote Originally Posted by kidamnesiac
    Looking at it again, the imidazole would certainly be more tricky as only one lone pair is not participating in the aromaticity at any given time although this changes with resonance so it would seem that it would be almost a wild card where you would get both the IAP-like effects and binding to either the 3 or 4 position electron pair seekers (at different times) with the same molecule.

    I'm sure this is most confusing, I'll try to chem draw up some pictures later in the week.
    I believe we are both thinking along the same lines,
    as to the imidazole wild card concept I suspect that once the lone pairs hydrogen bond with the hydrogen bond donor in DAT SERT or whatever then that will stabilise the imidazole in the tautomer that interacts most favourably with the donor as that will be the lowest energy state for the complex. Or to put it another way there is an energy penalty for not being hydrogen bonded. the imidazole also has the potential to be a H bond donor as well as an acceptor which complicates things compared to the oxazole.
    I am thinking that electronically at least 1-(benzoxaz-6-yl)-2-methylaminopropane (Benzoxazole numbering system) is very similar to MDMA, and retains the oxygen at the three postion which appears to be important for mixed serotonin and dopamine action.
     

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    #19
    Bluelight Crew fastandbulbous's Avatar
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    Yeah, but to be honest, I don't think it;ll make that much difference whether the 4 position is occupied by a carbon, nitrogen or oxygen atom; the 3 substituent seems to be the critical one. You could possibly even get away with a sulphur atom although that makes the possibility of the drug being an MAOI that much greater (sulphur atoms in the 4 position really play havoc with MAO by acting as competitive inhibitor. Sulphur is in the same column of the periodic table as oxygen, but is a larger atom which miust in some way prevent it taking up the active conformation).


    ps. Congrats on hitting the magic 10,000 post mark. Your "No Life" award will be in the mail shortly
    10,000 posts in 2 & 1/2 years - in a way that's pretty fuckin' sad and indicative of being a 'Billy no-mates'. It's a geeky job but someone's got to do it!
    Last edited by fastandbulbous; 06-02-2007 at 16:16.
     

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    #20
    Couldn't this be dangerous if it metabolises into an o-formamido phenpropylamine in vivo (eg carcinogenic)?
     

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    #21
    I wish I'd had a chance to try IAP + amphetamine. I tried IAP alone and with BDB - both times they were utterly useless. Almost dysphoric in a way. But I could tell the whole time that if I added some dopaminergic stimulant to it to make it euphoric, the synergy would be very much like MDA.
     

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    #22
    Quote Originally Posted by nuke
    Couldn't this be dangerous if it metabolises into an o-formamido phenpropylamine in vivo (eg carcinogenic)?
    if it did then it would possibly be carcinogenic, I don't think it will, there are several benzooxazole drugs out there and I don't think that metabolism opens the ring with these. benzooxazole appears a rather stable moetry.
     

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    #23
    IAP and MDPV!
     

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    #24
    Bluelight Crew fastandbulbous's Avatar
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    I don't have the paper anymore but nichols did investigate the dihydrofuran analog of MDMA I think it was the isomer with the 4 position oxygen replaced with 'Carbob' which fully substituted for the training drug. am i correct in thinking the 4 position o seems less critical for DAT SERT selectivity than the 3 o? If that is the case then that is where the N should go.
    Yeah, I've read & re-read it and the one wit the oxygen in te 4 position is less entactogenic than IAP due to poorer DAT (andNET) activity, the one with the oxygen on the 3 position was far better than IAP and not far behind MDA in DAT & NET activity and looks like it could be a real winner (many moons ago, in TR I posted the results of a bioassay of the 4-O compound - 5-(2-aminopropyl)-2,3-dihydrobenzofuran - and while enjoyab;le was nowt like MDA. unfortunately the 3-oxygen compound - 6-(2-aminopropyl)-2,3-dihydrobenzofuran is a lot harder to synth. Que ser sera)

    IAP and MDPV!
    Yeah, that would do the trick!
     

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    #25
    Quote Originally Posted by nuke
    Couldn't this be dangerous if it metabolises into an o-formamido phenpropylamine in vivo (eg carcinogenic)?
    contrary to what I said earlier , in the rabbit benzoxazole metabolises through ring rupture to give acetyl derivatives of the o amino phenol as well as free acetamino phenol and its gluconorides. o amino phenol is a suspected, though not very effective, human carcinogen, associated with bladder cancer.
     

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