Pharmacology of DOx

[Incunabula]

So, I´ve been wondering a lot about the pharmacology of the psychedelic amphetamines, specificaly the DOx compounds, as I would guess that DOI, DOC, DOM, DOB etc. will more or less share the same mode of action.

This is what Wikipedia had to say about DOM:

"DOM is a selective 5-HT2A, 5-HT2B, and 5-HT2C receptor partial agonist. Its psychedelic effects are mediated by its agonistic properties at the 5-HT2A receptor. Due to its selectivity, DOM is often used in scientific research when studying the 5-HT2 receptor subfamily. DOM is a chiral molecule, and R-(-)-DOM is the more active enantiomer, functioning as a potent agonist of the serotonin 5-HT family of receptors; mainly of the 5-HT2 subtype."

Yeah, well, being a psychedelic this really isn´t that surprising.

What I`m really wondering about is wether any of the DOx are known to release or inhibit reuptake of Dopamine or Norepinephrine. I mean, they are amphetamines, so some kind of shared pharmacology with regular amphetamine wouldn´t really be that odd.......?

The reason I´ve been thinking about this is because basically all of the DOx compounds are known to be very stimulating compared to other psychedelics. Could this stimulating side of of these amphetamines be caused by some kind of shared mode of action with the amphetamine structure in side these compounds?

Do we know anything about this? Hope I´m making sense.

Thanks

 

[pr0d1gy]

I think the stimulating effects are more likely caused by DOx's activating serotonin receptors that modulate other neurotransmitters like NA, DA and NMDA.

 

[Roger&Me]

I mean, they are amphetamines, so some kind of shared pharmacology with regular amphetamine wouldn´t really be that odd.......?

It would be odd, considering that the 2,5, and 4 subs drastically change the pharmacological profile of the molecule from that of amphetamine. The term amphetamine here is used to denote structural configuration, its not meant to group compounds by pharmacological action. If I was looking for parallels, I would first look at mescaline, TMA, etc before I would compare DOx to amphetamine.

 

[Incunabula]

I think the stimulating effects are more likely caused by DOx's activating serotonin receptors that modulate other neurotransmitters like NA, DA and NMDA.

So do you think they are activating these receptors in the same way as other psychedelics, tryptamines and 2c phenethylamines, do. Or do you think they are releasing dopamine for instance? (I asume that´s what you mean by DA?) I´m not sure I follow

It would be odd, considering that the 2,5, and 4 subs drastically change the pharmacological profile of the molecule from that of amphetamine. The term amphetamine here is used to denote structural configuration, its not meant to group compounds by pharmacological action. If I was looking for parallels, I would first look at mescaline, TMA, etc before I would compare DOx to amphetamine.

I see what you mean, but isn´t the definition of an amphethamine, that it´s a phenethylamine with a methyl group at the alpha-position? I´m thinking that this is causing a compound to have a certain SAR.
I mean aMT is a tryptamine with a methyl in the alpha position(right?). it´s the tryptamine version of speed, in a way, and it´s a triple releaser of dopamine, noradrenaline and serotonine....or so people say.
it´s also stimulating and longlived, like the DOx......

as to TMA, it´s also an amphetamine, and from what I read it´s also quite stimulating. I´ve been reading a lot about TMA-6, because I just got a gram, and from what I can read people are getting skin rushes and what not, that they actually compare with feelings from taking regular amphethamine. I´m guessing that at least the TMA´s actually do have some releasing, or inhibit reuptake, of either Dopamine or Norepinephrine to some degree.

I´m not saying I´m right. I´m asking a question

 

[PepperSocks]

I'm surprised there isn't any EC/IC50 numbers for the DOx's when it comes to monoamine release/reuptake inhibition. We know they agonize 5-HT receptors, but nothing of the release/inhibit nature. I'm also quite curious.

From the "radioligand assay inside me" it feels like Roger said. I would be surprised if DOx's had any dopamine release ala amphetamine. LSD is stimulating, most psychedelics are, but I doubt they do it through dopamine release.

 

[Incunabula]

Okay, cool

So you think it´s the same with the TMA`s? Peppersocks.

I must admit I have a hard time accepting it....

 

[PepperSocks]

I've never had any TMA's so I'm not sure of their effects. I think the best one to compare it to would be TMA-2; seeing that is has the 2,5-DM thing, with a 4-substitution. TMA-2 is basically "DOMethoxy"; whereas DOM has a methyl group on the 4 position.

Are there any EC/IC numbers for the TMA's? I'm to tired from this week to do any high level searching at the moment.

What's the deal with DOx's non-alpha methylated analogues?

 

[sekio]

I think some of the 2c-* and tryptamine drugs are SRI drugs.

The other thing to note is the fcat that drugs of this nature (phenethylamines) usually have affinity for alpha or beta adrenergic receptors, activity at those is probably responsible for the stimulatory nature of the high...

 

[PepperSocks]

LOL, I completely forgot that DOx's non-alpha methyl analogues are the 2C-x's.. Duh :D

 

[Incunabula]

I think some of the 2c-* and tryptamine drugs are SRI drugs.

The other thing to note is the fcat that drugs of this nature (phenethylamines) usually have affinity for alpha or beta adrenergic receptors, activity at those is probably responsible for the stimulatory nature of the high...

That´s pretty interesting. Does anybody know any more about this?

So could this affinity for alpha or beta adrenergic receptors cause release of adrenaline or noradrenaline?

 

[Incunabula]

LOL, I completely forgot that DOx's non-alpha methyl analogues are the 2C-x's.. Duh :D

Yeah, and the 2c analogues are by far not as long lived or stimulating. See my point, it´s not that strange to think that it´s the alpha methyl part of the molecule that´s responsible for the stimulation....

 

[Cortexiphan]

As for transporter inhibition there is some data in TS Rays paper "Psychedelics and the human receptorome" on DOx and 2C-X compounds although the validity of ths paper has been questioned. I have never seen any data on neurotransmitter release by DOx/2C-x although there is a nice table on the wikipedia page for releasing agents.

 

[Roger&Me]

I see what you mean, but isn´t the definition of an amphethamine, that it´s a phenethylamine with a methyl group at the alpha-position? I´m thinking that this is causing a compound to have a certain SAR.I mean aMT is a tryptamine with a methyl in the alpha position(right?). it´s the tryptamine version of speed, in a way, and it´s a triple releaser of dopamine, noradrenaline and serotonine....or so people say.

Well yeah, I mean also if you look at eg. DOM --> ARIADNE you'll see that extending the alpha methyl to an alpha ethyl will drastically decrease activity -- so the alpha-methyl is fairly important. That's not the point though, amphetamine and psychedelic amphetamines possess few pharmacological similarities.

It's absolutely not logical to say that because DOx are technically amphetamines, they should share pharmacological similarities with amphetamine. Substitution of the ring drastically alters the affinity of the molecule for 5-HT and catecholamine sites (binding at catecholamine sites necessitates the meta oxygen's lone pair electrons are anti to the 4 position substituent), hence the rich diversity in the pharmacology of amphetamines (and why DOM is selective for 5-HT receptors because the meta oxygen's lone pair electrons orient themselves syn to the 4-position substituent!) Amphetamines actually span three distinct classes of drugs: psychedelics, entactogens, and stimulants.

But what should first give you an indication that DOx have drastically different receptor interaction from amphetamine is the fact that (S)-amphetamine is the more active isomer, while in the case of eg. DOM the (R) isomer is more active. This shows that they most likely interact with structurally unrelated receptor systems.

Furthermore, extending the alpha-methyl of amphetamine to an ethyl group retains activity as a norepinephrine releasing agent. As I said before, extending the alpha chain of DOM as seen in ARIADNE results in almost complete inactivity, noradrenergic or otherwise.

As you can see, there are many reasons why its not useful to compare DOx to amphetamine.

as to TMA, it´s also an amphetamine, and from what I read it´s also quite stimulating. I´ve been reading a lot about TMA-6, because I just got a gram, and from what I can read people are getting skin rushes and what not, that they actually compare with feelings from taking regular amphethamine. I´m guessing that at least the TMA´s actually do have some releasing, or inhibit reuptake, of either Dopamine or Norepinephrine to some degree.

It's not useful to group "the TMAs" all together and suggest that they all have catecholamine releasing properties, because of how the amphetamine SAR works.... Something like TMA-6 most likely does have stimulant activity because it possesses no meta-oxygens, while TMA-2 is a quintessential psychedelic because it posseses 1 freely rotatable meta oxygen; TMA's effects are not desirable in comparison to TMA-2 because it possesses 2 meta oxygens rather than 1.

Just compare 2,4-DMA to 2,5-DMA to 3,4-DMA: the 2,4 product is amphetamine-like, the 2,5 product induces mydriasis and rapid heart beat, and the 3,4 product is mescaline-like in activity. It's crystal clear that in order to have "mescaline-like" hallucinogenic activity, there must be exactly 1 meta oxygen on a freely rotatable substituent such that its lone pair electrons may orient themselves syn to the para substituent. This is further evidenced by the fact that if you fuse the ring structure of 3,4-DMA together to form MDA, much hallucinogenic activity is lost because the m-oxygen's lone pair electrons are then oriented anti to the para sub.

For yet even further evidence of this phenomenon, compare 5-APDB to 6-APDB. As one would expect, since 6-APDB possesses a meta-oxygen whose lone pairs are anti to the para substituent (LOL I'm starting to feel like a broken record) it is more selective for catecholamine sites while 5-APDB is more selective for 5-HT release.

 

[Epsilon Alpha]

One interesting thing to note is that it appears that the metabotropic glutamate receptors appear to have a large role in amphetamine's monoamine releasing action. I wouldn't be surprised if the DOX series shared some activity at these receptors that plays into the subjective effect, but it also wouldn't surprise me if they were weak reuptake inhibitors for one or two monoamines as well.

http://www.nature.com/npp/journal/vaop/ncurrent/full/npp2011145a.html

 

[PepperSocks]

Well yeah, I mean also if you look at eg. DOM --> ARIADNE you'll see that extending the alpha methyl to an alpha ethyl will drastically decrease activity -- so the alpha-methyl is fairly important.

It's important in the sense that it can't be longer than methyl, but not having it at all also works (2C-x)

That's not the point though, amphetamine and psychedelic amphetamines possess few pharmacological similarities.

It's absolutely not logical to say that because DOx are technically amphetamines, they should share pharmacological similarities with amphetamine.

Ya, I found this out not long ago. I was experimenting with low dose DOI (<0.5mg) as a cognitive stimulant ala amphetamine, but it did not work. At 0.5mg the only thing it stimulated was low dose psychedelic libido; no work got done

Any psychoactive dose is psychoactive in a psychedelic way; not a plain stimulant way.

 

[Roger&Me]

It's important in the sense that it can't be longer than methyl, but not having it at all also works (2C-x)

Indeed. And this is yet another clue that DOx and amphetamine interact with different receptor systems. :D eg. when you remove the alpha-methyl group from DOx they retain activity as 2C-X, but removing amphetamine's alpha-methyl yields phenethylamine which is not centrally active.

IIRC in the case of 2C-x and DOx, really the only thing that the alpha-methyl does is sterically restrict the free rotation of the ethylamine side chain. Classical psychedelics become more potent as they become more planar (look at eg. 2C-B-FLY --> BRDFLY). That's most likely why LSD is so potent, because it is an extremely planar molecule -- even its unconjugated rings are sandwiched between planar systems so they can't adopt non-planar conformations.

Another thing, slightly related, that I've been wondering: is there any significant degree of keto-enol tautomerism of LSD's amide? If this occurs, LSD's D ring is actually fully conjugated with all carbons sp2 hybridized, and thus it is completely planar! If this is the case, then electrons would be delocalized across the C ring as well, and the entire molecule would be completely flat. Even if this doesn't occur though, the C and D rings of LSD would still be extremely planar even when not fully conjugated.

 

[Incunabula]

Thanks a lot for the answers

 

[MattPsy]

Another thing, slightly related, that I've been wondering: is there any significant degree of keto-enol tautomerism of LSD's amide? If this occurs, LSD's D ring is actually fully conjugated with all carbons sp2 hybridized, and thus it is completely planar! If this is the case, then electrons would be delocalized across the C ring as well, and the entire molecule would be completely flat. Even if this doesn't occur though, the C and D rings of LSD would still be extremely planar even when not fully conjugated.

Yes, I believe the active conformation of LSD is indeed planar, and not just planar, but restricted to this as well. The N-benzyl PEAs should be [mostly] planar too, but they are not locked into this conformation.

 

[PepperSocks]

Indeed. And this is yet another clue that DOx and amphetamine interact with different receptor systems. :D eg. when you remove the alpha-methyl group from DOx they retain activity as 2C-X, but removing amphetamine's alpha-methyl yields phenethylamine which is not centrally active.

I thought for us PEA isn't active because it gets broken down long before finding a synapse but endogenous PEA is an important neurochemical (don't think it's an actual neurotransmitter with it's own receptor system). I'm not sure on the validity of the science but it's said that PEA levels are increased when we fall in love and schizophrenics have higher PEA levels than non-schizophrenics. Again; not sure on the validity of those claims but I've read both more than once.

AFAIK endogenous PEA is centrally active but if we try to ingest exogenous PEA it gets broken down by MAO. I'm not sure what the deal is if you try to vape/snort it to bypass 1st pass metabolism.

I've found 2g along with Kava (mild MAO-B inhibitor) has some effect, paradoxically it makes the Kava more relaxing/sedating.

My point being once PEA is behind the BBB I'm pretty sure it has an action. However if you substitute the ring on PEA (2C-x) it doesn't get metabolized by MAO and is very centrally active via oral admin.

 

[ebola?]

Off-topic:

AFAIK endogenous PEA is centrally active but if we try to ingest exogenous PEA it gets broken down by MAO. I'm not sure what the deal is if you try to vape/snort it to bypass 1st pass metabolism.

MAO exists in the blood in high concentrations, so it's not first pass metabolism that's the issue per se. In careful conjunction with inhibition of MAOB, phenethylamine's effects resemble amphetamine's (albeit being even more selective for norepinephrine) (one needs to research things exhaustively before trying this). Both amphetamine and phenethylamine are agonists at TAAR sites.

ebola