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Psychedelics: how far can we go?

Rorthron

Rorthron

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I was intrigued by the recent Fentany analogue thread, which focused on extremely potent mu-opioid receptors. Carfentanyl, for once is active at dosages levels of 1 ug, and probably there are others even more potent. The efficiency of such a product is amazing. It passes the BBB quite easily, is apparently immune to all the enzymatic metabolic processes in the blood and liver and binds dramatically to the mu-opioids in the brain.

Now my question is, is it conceivable the existence of similar products for the 5HTxx receptors? namely 5HT2a. For a long time LSD appeared as the champion, but recently with the DragonFly compounds and even more recently the x-NBOMe compounds, we are reaching a very similar level of potency. How far can the specificity of psychedelics hallucinogenic compounds go? is it conceivable 1 ug effective dose?

[As a side note, I was of course thinking of something like Br-DragonFly-NBOMe, but is probably a dumb idea...]

Of course, the 5HTxx receptors are a different beast altogether, as there are many (13, at least) and many compounds active in one receptor are active in many others, but this might even be a further avenue of exploration...

But really, how far can we go? How potent can synthetic compounds become to produce "the ultimate psychedelic"?
 
Is potency, with regard to how much you must ingest to achieve the desired effect, really the ultimate measure of a psychedelic? I don't particularly care if I have to take 1uG, 1mG or 1G. What matters to me is the quality of the experience it produces.
 
AfterGlow said:
Is potency, with regard to how much you must ingest to achieve the desired effect, really the ultimate measure of a psychedelic? I don't particularly care if I have to take 1uG, 1mG or 1G. What matters to me is the quality of the experience it produces.
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^this. Potency (ie. how much you have to take a substance) has nothing to do with the qualitative "strength" of the substance, ie. a less potent substance can produce a stronger psychedelic experience than a more potent one.

For an example, DMT in my experience produces one of the strongest and deepest psychedelic experiences, despite not being very "potent" on a mg-to-mg basis.
 
Note, I'm not talking about the quality of the psychedelic experience. There are already many substances capable of producing profound and enjoyable feelings and emotions. My question was a pure quantitative and scientific one. Can actual science produce 5HTxx agonist compounds with the similar potency that carfentanyl shows for mu-opioid receptors?
 
fryingsquirrel said:
The NBOMe versions of DOx chemicals are inactive,
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hmmm... that's really interesting. Do you have a reference for that?[edit: just found it!:Braden MR, Parrish JC, Naylor JC, Nichols DE. Molecular interaction of serotonin 5-HT2A receptor residues Phe339(6.51) and Phe340(6.52) with superpotent N-benzyl phenethylamine agonists. Molecular Pharmacology. 2006 Dec;70(6):1956-64]


to dread: Thanks for the info, but I've been digging them up and I believe none of the compounds you mentioned are even as powerful as LSD
 
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I'd be suprised if they're inactive - DOI-NBOMe has affinity comparable to plain DOI (0.78nM at h5-HT2A) and much higher selectivity over 2C (27x).

The highest affinity so far is 25I-NBDHF (dihydrofuran) with 0.026nM! That's 15x higher than LSD, though I suspect it's actually still not as potent as LSD, but probably close.
 
Phener said:
really?
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Yes. In the NBOMe-2C series, the activities are reversed compared to the 2C series. That is, the smaller 4-substitutents have higher activity with the NBOMe-2C-Xs, but the larger 4-substituents have higher activity with the 2C-Xs. Thus, NBOMe-2C-C is the most potent of the NBOMe-2C-Xs, but 2C-C is one of the weakest 2C-Xs. Since the CF3 group is as large as or larger than an iodine, the activity of the NBOMe-2C-TFM is probably about that of NBOMe-2C-I. Potent, yes, but not stronger than the other NBOMe-2Cs. It seems that the NBOMe-2Cs are much more sensitive to steric effects than the 2C-Xs or DOXs. For example, it was also found that the NBOMe-DOXs are much weaker than the DOXs.
 
Hammilton said:
Yeah, why not try to make chemical weapons out of psychedelics.
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good point there. nothing good can come from a quest for ultra potent drugs. either someone will try to make a lot of money, or try to do something evil with it (probably both). If one is focused on useful or interesting compounds and one of them happens to be potent, so be it.

did the OP mention what he would do with these compounds?
 
Slapdragon - none that I know of, I think it's mostly from 'unofficial in vivo experiments' :)

There are different values for DOI-NBOMe in Nichols 2006 molecular interaction of 5HT2A receptor residues with superpotent N-benzyl phenethylamines - the Ki is about double that of DOI, the EC50 is higher and the intrinsic activity lower, so that bit at least is supported by literature.
 
I can imagine a terrorist attack with ultra-potent psychedelics, sending something like ten thousand people on a trip... Didn't the US army do research with psychedelics in the 50s/60s to find something suitable to use as a "psycho-gas" in chemical warfare, or was it truth serum?
 
onmyway said:
did the OP mention what he would do with these compounds?
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I don't want to do anything with it. I don't even work on synthesis nor have specific interest on ultra potent compounds! My question was really academic. If carfentanyl (binding to mu-opioid receptors) is active on 1ug dosages (and as such most probably useful as a chemical weapon), is it conceivable to reach similar potency for 5HT2a agonists?

I'm not assuming it would even be useful. It's like inquiring if an atom bomb is possible, without the intent of doing one.

However, it such compound would exist, in which chemical family would one search for them? Phenylethylamines, Lysergamides? Also would the N-alkyl substitutions on Phens be the way to go? Or perhaps, further substitution testing in lysergic compounds?

If Dr Nichols was a member of this forum he could perhaps provide some valuable insight!
 
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