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Question about how MDMA works

Ham-milton

Ham-milton

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Jul 20, 2007
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Hey, I was thinking this afternoon about how MDMA basically does what it does to Serotonin in the say that Amphetamine does the same to Dopamine.

I've got the flu really bad today, my body is just racking from pain and nausea, so some of this might not make sense. If it doesn't, let me know.

I was thinking about how MDMA is basically amphetamine with a 5 sided ring pointed out, making it look a bit like a misdrawn tryptamine, with the wrong 5-sided ring, and the chain put in the wrong.

That made me wonder if it's activity was due to having an indole-ish structure, like serotonin.

What if an MDMA-analogue was synthesized that was an indole. Has it been done? Is it active?

What about 1,3 benzodioxole analogues of tryptamines?
 
Yes...

It is a bit strange that MDMA is identified as a 5-HT2 potent receptor binder, and thus it's psychotomimetic activity is via the serotonin pump rather than the dopamine pump, which at casual glance makes more sense.
The shulgins have looked at the "reversed benzodioxole" analog in the MDMA series and if i'm not mistaken (i'm taking this on long term memory) there was little activity to this analog, which is again strange , but it is well known that even some very simple changes in a molecule can wipe out activity.
Now if one looks at bufotenine, the 5-methoxy,NN-dimethyltryptamine or "toad poison", your idea would be to add a 6-oxygen and tether the 5,6 oxygens on the benzo ring of the indole with an ethyl bridge, along with the addition of a methyl group, alpha to the nitrogen on the 3-ethyldialkylamino side chain of the indole. My gut feeling is that you would have something to recon with, but without human data from a known synthesis and testing, we are in murky waters. I have also wondered about "5-NN'dialkylamino-ethyl indole" itself. Anyone have any real data on these ideas?
 
MDMA 5ht agonism is a minor component of its action it is an effective reverse serotonin transporter as well as being able to reverse DA and NE causing major increases in extracellular concentrations of all three of these neurotransmitters. it seems to me that MDMA vs methylone differ only by the much greater ability of mdma to increase NE, they are pretty similar at releasing DA and SE.

what would the reversed benzodioxole be? I am guessing the benzoisofuran, benzene -CH2-O-CH2- as opposed to -O-CH2-O- (methylenedioxy), benzoisofuran is not a very stable creature at all.

as for 5 dialkylaminoethyl indole, see glennons papers on the isotryptamines and stoll and hellers work on psilocin isomers, they either mention them or reference to papers that do, I am too lazy to dig up these refs.
 
Methylone differs from MDMA mostly by it's VMAT2 binding AFAIK, which is on the order of 10 times lower.
I haven't seen anything showing a much greater tendency toward NE release :/ ?
Argh, ok I guess I betetr dig out the references, I was being lazy...

IC50 values (uM) for drug inhibition of monoamine uptake
[3H]5-HT / [3H]DA / [3H]NE / VMAT2([3H]5-HT)
Methylone 5.75 +/- 0.68 / 0.819 +/- 0.168 / 1.22 +/- 0.13 / 165.6 +/- 11.7
MDMA 2.14 +/- 0.34 / 0.478 +/- 0.107 / 1.38 +/- 0.10 / 12.7 +/- 1.6

Inhibition of plasma membrane monoamine transporters by
b-ketoamphetamines
European Journal of Pharmacology 381 (1999) 63–69

Ok so yeah I think this supports what I remembered unless i'm missing something obvious hehe.
 
MattPsy said:
Methylone differs from MDMA mostly by it's VMAT2 binding AFAIK, which is on the order of 10 times lower.
I haven't seen anything showing a much greater tendency toward NE release :/ ?
Argh, ok I guess I betetr dig out the references, I was being lazy...

IC50 values (uM) for drug inhibition of monoamine uptake
[3H]5-HT / [3H]DA / [3H]NE / VMAT2([3H]5-HT)
Methylone 5.75 +/- 0.68 / 0.819 +/- 0.168 / 1.22 +/- 0.13 / 165.6 +/- 11.7
MDMA 2.14 +/- 0.34 / 0.478 +/- 0.107 / 1.38 +/- 0.10 / 12.7 +/- 1.6

Inhibition of plasma membrane monoamine transporters by
b-ketoamphetamines
European Journal of Pharmacology 381 (1999) 63–69

Ok so yeah I think this supports what I remembered unless i'm missing something obvious hehe.
Click to expand...

check out the june 2007 japanese paper on the toxicology of MBDB Methylone and other RC's it seems to indicate that using the same assay MDMA was 10x more effective in vitro.. I will post the refs when
get the time
 
Wow ok, I will be sure to give that a look, very interesting indeed :) . Thanks.
 
scuse..

So what you are saying is that MDMA is a reuptake inhibitor at 5-HT, DA and NE sites? From the numbers it looks like mDMA is more effective at dopamine reuptake inhibition with IC50 at 478 nM, sorry for my ignorance, as i said in one of my posts, i'm out to pasture now and don't have access to the literature anymore. Funny, if you look at the structure of the antidepressant, Effexor, it has many structural resmblances to the compounds that you discussed. Knock off a methyl on the nitrogen replace the 4-methoxy with a 3,4 methylendioxy and reduce off the hydroxyl group and i bet you've got a trippy compound!
And vector, what i was talking about was a 6-dialkylamino-(beta)methyl-ethyl-1,4-benzodioxole, not a benzofuran or the fleeting isobenzofuran.
 
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Yeah it acts as a triple reuptake inhibitor (so monoamines build up in the synapse), but it also has actions on VMAT2 (so the monoamines get pumped into the synapse faster), but it also seems to have a unique effect on the 5-HT reuptake transporter because not only does it inhibit 5-HT reuptake from the synapse, it seems to make it run in reverse... pumping the 5-HT it's already removed back into the synapse! I guess there must be a distinct binding site it (MDMA and friends) fits into to change the conformation (and thus, activity) that dramatically.

But from what vecktor is saying there appears to be new research which shows MDMA to be much more effacious at increasing synapse concentration of NE, too. I forgot to look for it last night, I will look at it sometime today.
 
Are any other compounds with similar VMAT2 actions known? Is there something endogenous that does the same (probably at a reduced level though)? It would make sense that there is.

Stoned inspiration probably led me to just assume that SE was that compound, but that seems unlikely in the clear, sober light of day.
 
TBZ, DTBZ, Lobeline, and reserpine are well-known VMAT2 ligands. d-amphetamine is of course another one, but it seems to bind at a different site.

Vesicular Monoamine Transporter 2: Role as a Novel Target for Drug Development
The AAPS Journal 2006; 8 (4) Article 78, 682-692

Characterization of a Series of 3-Amino-2-phenylpropene Derivatives as Novel Bovine Chromaffin Vesicular Monoamine Transporter Inhibitors
J. Med. Chem. 2003, 46, 2599-2605

^ Are some papers I have, no doubt there will be newer and/or better ones, interesting nonetheless.

I don't know about endogenous ligands but as you say it would make sense that there are :/ .
 
d-amphetamine seems to be pretty dopamine specific. mdma seems to be pretty SE specific, though. I was thinking that mdma's methylenedioxyphenyl group mimiced serotonin, the way that (theoretically) the benzofuran group does with the hemifly's.
 
reverse transporter activation of SERT and DAT and NERT is it seems the most important aspects of MDMA's action I would expect it causes phosphorylation of the transporter to make it internalise the transporter pocket when empty. VMAT just dumps more monoamines into the cytoplasm, from the vesicles. once in the cytoplasm the transporter proteins DAT SERT etc can reverse transport it into the synapse.
The reuptake inhibition effects of MDMA seem limited.
 
Ham-milton said:
Are any other compounds with similar VMAT2 actions known? Is there something endogenous that does the same (probably at a reduced level though)? It would make sense that there is.

Stoned inspiration probably led me to just assume that SE was that compound, but that seems unlikely in the clear, sober light of day.
Click to expand...


Well methamphetamine is similar, only the 5HT component of activity is much less than with MDMA. Also explains why in pills, meth is added so less MDMA is required (it - MDMA - being the more expensive & harder to source precursors for), but without seriouslydamaging the 5HT mediated effects that. Plain ol' amphetamine has bugger all effect on serotonogic activity & as such is a piss poor additive
 
well, interestingly, in the April 2007 New Scientist, there's an article that says that when oxytocin receptors in the brain are blocked the increased socialability is almost entirely negated.

Are there any other drugs known to raise *brain* levels of oxytocin? Things that raise it in the blood don't work (probably bbb permeability issues)
 
hence why i noted this particular aspect above

5HT1a agonism is likely what is responsible here for this particular oxytocic modulation again as noted above
 
Yeah, but 5HT1a agonists don't induce MDMA-like openness. 8-OH-DPAT and Alnespirone are anxiolytics, not exactly pro-social drugs in the sense that MDMA is- so I don't think 5HT1a agonism is the cause.

Would be interesting to try a 5HT1a selective antagonist w/ MDMA to see, though.
 
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