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Potential to make ultrapotent MDMA like Ergot derivetives

T

toxide

Bluelighter
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Mar 21, 2006
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There are many ergot compounds out there, 1/2 seem to be potent 5HT agonist(psychedelic) and the other 1/2 are fairly potent dopamine agonists, are there any or could there be ones that have stong effects on both serotonine and DA?

ALSO>>> After some reading I found that Cabergoline and Pergolide agonize 5HT2 receptors aswell as DA. Would these compounds have psychedelic FX? I think it said they were potent 5HT2b agonists er sumthing.
 
in short no.
MDMA is a NE DA and SE releaser and reuptake inhibitor not an agonist, and this is its primary mode of action, none of the ergolines are releasers or to any extent reuptake inhibitors. Agonists are much different to indirect agonists. This has been covered before on this forum.
Also the priviledged structure for dopamine agonism is not the same as the priviliged structure for 2a agonism, making a hybrid 5ht2a, DA agonist rather tricky.
 
eh?

Lysergic acid diethylamide (LSD) is a partial agonist of D2 dopaminergic receptors and it potentiates dopamine-mediated prolactin secretion in lactotrophs in vitro
by
Giacomelli S, Palmery M, Romanelli L, Cheng CY, Silvestrini B
Institute of Pharmacology and Pharmacognosy,
University of Rome La Sapienza, Italy.
Life Sci 1998; 63(3):215-22

ABSTRACT
The hallucinogenic effects of lysergic acid diethylamide (LSD) have mainly been attributed to the interaction of this drug with the serotoninergic system, but it seems more likely that they are the result of the complex interactions of the drug with both the serotoninergic and dopaminergic systems. The aim of the present study was to investigate the functional actions of LSD at dopaminergic receptors using prolactin secretion by primary cultures of rat pituitary cells as a model. LSD produced a dose-dependent inhibition of prolactin secretion in vitro with an IC50 at 1.7x10(-9) M. This action was antagonized by spiperone but not by SKF83566 or cyproheptadine, which indicates that LSD has a specific effect on D2 dopaminergic receptors. The maximum inhibition of prolactin secretion achieved by LSD was lower than that by dopamine (60% versus 80%). Moreover, the fact that LSD at 10(-8)-10(-6) M antagonized the inhibitory effect of dopamine (10(-7) M) and bromocriptine (10(-11) M) suggests that LSD acts as a partial agonist at D2 receptors on lactotrophs in vitro. Interestingly, LSD at 10(-13)-10(-10) M, the concentrations which are 10-1000-fold lower than those required to induce direct inhibition on pituitary prolactin secretion, potentiated the dopamine (10(-10)-2.5x10(-9) M)-mediated prolactin secretion by pituitary cells in vitro. These results suggest that LSD not only interacts with dopaminergic receptors but also has a unique capacity for modulating dopaminergic transmission. These findings may offer new insights into the hallucinogenic effect of LSD.
 
how do you get fron d2 agonism to DA SE NE release? which is what the original poster was seeking, a compound like MDMA.

2a agonism indirectly gives some dopamine release.
in order to get decent release it has to be transported by dat sert or net, and ergolines appear too big to do that

and then you are stuck.
:\

lisuride is a much more potent d2 agonist than LSD is it any more MDMA like???
what is interesting is that it has nearly the same binding affinity as LSD at h5HT2a but is much less effective as an agonist, and seems primarily to trigger the wrong second messenger system.
still this is not what is sought.

edited a bit having engaged brain..
 
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yea, i wasn't saying that the mdma mimicking is possible but you said it is tricky to get agonism from the ergoloids when there is, even from lsd
 
^ good point my bad :)
I thought for some reason that the 9-10 dihydro was needed for potent dopamine agonism where the 9-10 dihydro abolishes 5HT2a agonist activity to all intents and purposes. apparently not.

I will have to read the paper properly.

The numbers in the abstract indicate this DA partial agonism will be significant at the kind of concentrations required for 5HT2a/ 2c agonism, same ball park anyways.

the DA agonist LSD thing was big in the mid 70's and was kind of shot to peices by the mid 80's. I think the consensus was yes it is there but it really isn't important, due to the lack of effect dopamine antagonists had on acid induced place preference amongst other things.
 
I believe they train the rats to go to a certain area of the cage under the influence of a training drug, then dose them again the theory being that they will go to that area again. so the theory goes if an antagonist disrupts this then the antagonist is interfering with the drug action or the cue the rats are using to discriminate between the drugs, , a bit like nichols' 2 lever pressing rats.
variations on this idea include observing stereotyped behaviours which are supposed to indicate one kind of drug action and so forth.
 
ah, yea, i always understood the lever rats, that makes that clear, thanks
when i die, i want to be reincarnated as a nichols rat
 
vecktor said:
MDMA is a NE DA and SE releaser and reuptake inhibitor not an agonist, and this is its primary mode of action
Click to expand...
I thought MDMA was also a weak HT agonist, which accounted for its hallucinogenic properties?
 
samadhi_smiles said:
I thought MDMA was also a weak HT agonist, which accounted for its hallucinogenic properties?
Click to expand...

I put 'primary' mode of action, MDMA has very weak 5ht agonist action but this is probably due on the whole to demethylation to MDA which is a more active agonist. I don't think secondary amines are very effective at 2a at all, other than the N-benzyls and who knows whether they are really agonists.
MDMA also has a whole other raft of effects though I doubt they contribute much to the main effects.
so if one was designing nexcstacy (TM) getting the release reuptake profile would be half the battle, then getting it to be non-neurotoxic would be the rest.
sadly I think it is impossible unless one of the indans can be persuaded to release DA and NE..
V
 
Can you point me toward the 'raft of other effects' (at least a keyword to search). All I'm finding is the triple effect (reuptake inhib, monoaminerelease, and agonism).

Its so interesting when one chemical does so many different things in the brain!
 
vecktor: Isn't it impossible to make Nextacy (haha, love that, nice name ^_^) non-neurotoxic?
It would be possible if it were actually MDMA's breakdown or whatever that caused the neurotox, but isn't it currently understood to be caused by the uptake of DA by SERT followed by the degradation by MAO and subsequent peroxide formation and so oxidative damage?
If so I can't see how you can get around it completely. By limiting a big 5-HT drop (by making it purely a reuptake inhibitor instead of being a releaser too, to avoid the "Dump" activity it has..) you could limit it (because there would be more 5-HT around in the synapse, so SERT wouldn't take as much DA up by "accident") but I can't see how you'd avoid it completely.
Then again, maybe just lowering it to a more manageable level would prevent damage.
Unless i'm not up to date with the current understanding of how the neurotox happens?
 
^ sadly I think you are right, and suspect Nexcstacy (TM) working in the same way as MDMA will be neurotoxic. unless it can be cleverly engineered. assuming of course the mechanism of neurotoxicity is oxidative stress caused by excessive DA, or some other fundemental feature of entactogens (mixed da se net releaser-reuptake inhibitors).
though I hope there are way around this problem.
I haven't seen data for methylone neurotoxicty yet, I suspect it is. Does anyone have any info?
 
I was reading the human pharmacology of MDMA pdf up there, and on page three it states that the s isomer is the cause of the stimulant and empathic properties and r the cause of the hallucinogenic effects. Has there ever been recorded use of one isomer alone? If so what were the qualitative differences between racemic, s, and r experiences?
 
Yes, in PIHKAL.....Shulgin has literature on all three (R, S, R/S). According to Shulgin, the R-isomer is nearly completely inactive...or at least has none of the MDMA-like effects. I think that paper is incorrect.
 
from Pihkal
http://www.erowid.org/library/books_online/pihkal/pihkal109.shtml
(with 100 mg of the "R" isomer) There were the slightest of effects noted at about an hour (a couple of paresthetic twinges) and then nothing at all.

(with 160 mg of the "R" isomer) A disturbance of baseline at about forty minutes and this lasts for about another hour. Everything is clear by the third hour.

(with 200 mg of the "R" isomer) A progression from an alert at thirty minutes to a soft and light intoxication that did not persist. This was a modest +, and I was at baseline in another hour.

(with 60 mg of the "S" isomer) The effects began developing in a smooth, friendly way at about a half-hour. My handwriting is OK but I am writing faster than usual. At the one hour point, I am quite certain that I could not drive, time is slowing down a bit, but I am mentally very active. My pupils are considerably dilated. The dropping is evident at two hours, and complete by the third hour. All afternoon I am peaceful and relaxed, but clear and alert, with no trace of physical residue at all. A very successful ++.

(with 100 mg of the "S" isomer) I feel the onset is slower than with the racemate. Physically, I am excited, and my pulse and blood pressure are quite elevated. This does not have the 'fire' of the racemate, nor the rush of the development in getting to the plateau.

(with 120 mg of the "S" isomer) A rapid development, and both writing and typing are impossible before the end of the first hour. Lying down with eyes closed eliminates all effects; the visual process is needed for any awareness of the drug's effects. Some teeth clenching, but no nystagmus. Excellent sleep in the evening.
Click to expand...

R amphetamines are always the less active as stimulants, though more active as hallucinogens, and the idea that the stimulation comes from the R is a bit odd from pihkal it seems clear that the R isomer is pretty much inactive at 200mg on its own but it seems to have a synergy with the S, the logic works like this,

a 120mg dose of MDMA racemate would be expected to be 60mg of the S and 60mg of the R, I have not seen any evidence that the reductive amination of MDP2P the most common synth, produces anything other than a 50:50 mix.
the 60mg dose of the S enantiomer above doesn't appear to have the same level of effects.

Also 200mg or the R seems only to be threshold active on its own but is possibly enhanced by the S, an interesting experiment would be 20 mg of S and 100mg of R or perhaps a few experiments where the total dose is kept constant and the ratio of the two enantiomers is altered from pure s through to pure r through a couple of intermediate mixtures.

The half life of the R enantiomer is longer than the S enantiomer, because people take multiple doses over a period of time, gradually the blood plasma level of the R enantiomer will increase, so say by the second dose there will be much more R left over from the first dose, perhaps a reason why side effects increase with multiple dosing??

who knows I'm just thinking out loud
V
 
Re: Place preference. That one is really simple. You put a rat in a room, that is connected to another room through a hole in the wall. One room has one kind of patterns on the wall, the other room has another pattern. The rat figures "oh yeah, I can move from one room to the other, through this door, and the two rooms look different".

Then you give the rat Drug A, put it is one particular room and close the hole between the rooms. The a couple days later, you give it saline and put it in the other room. Repeat.

Then you put the rat back in the chamber, open the door. If the rat "liked" the drug, he'll spend more time in the room he was dosed with it in. Some drugs give you conditioned place aversion, so the rats specifically avoid the room they got the drug it.
 
vecktor said:
^ sadly I think you are right, and suspect Nexcstacy (TM) working in the same way as MDMA will be neurotoxic. unless it can be cleverly engineered. assuming of course the mechanism of neurotoxicity is oxidative stress caused by excessive DA, or some other fundemental feature of entactogens (mixed da se net releaser-reuptake inhibitors).
though I hope there are way around this problem.
I haven't seen data for methylone neurotoxicty yet, I suspect it is. Does anyone have any info?
Click to expand...

Cathinone and methcathinone are neurotoxic, I'd eat a Chinese peasant's hat with soy sauce if it wasn't too.

You're probably right about the neurotoxicity. I have a feeling that it's mostly like this: DA/NE release + peripheral and central hyperthermia (exacerbated by SER release or 5HT2A/C receptor modulation) -> Generation of free radical oxidative species (esp. superoxides) -> Apoptosis, terminal damage, and enzymatic system destruction. It seems mostly characteristic of NA/DE/SER releasers rather than reuptake inhibitors (cocaine seems kind of benign compared to MDMA or methamphetamine centrally).

I have had great success at reducing any sort of MDMA comedown by using huge amounts of antioxidants, typically ascorbic acid (3g), n-acetyl-cysteine (1g), idebenone (100mg), inosine (1g), and r-ALA (100mg), prior to, at the end of, and for a couple days after MDMA administration. It seemed similarly effective with methamphetamine, but I wouldn't push my luck with that stuff.

It's already been shown that AET seems to cause SER reductions similar to MDMA, so I'm not sure if there's much specifically due to the structure of MDMA and related amphetamines themselves..

As far as 'Nexstasy', perhaps something more potent with an antioxidant that is catabolically seperated in vivo in the structure might work (n-idebenone-MDMA? bond idebenone's alcohol group at MDMA's amine, hah...).
 
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