Psychedelics: how far can we go?

[skillet]

I mean N-benzyl dihydrofuran - think 2,3-methylenedioxybenzyl with the 3-O replaced with C. Yeah it does seem to have the highest affinity, 0.026nM in the thesis ^

 

[Astavats]

You're right, I just noticed NBDHF is in it as well; as you were.

 

[Solipsis]

Alright I got the structure clear, thanks very much.

I guess it's the constrained structure again that does the trick of making it sort of invincible, lol. Like TCB-2 and the flies... or perhaps thats flawed logic. It's probably a combination of the fact that heterocycle structures that are constrained are less susceptible to reaction / attack positions and with things like the Fly series a change of conformational position i.e. the 2 and 5 O's get bent to a more permanent place instead of flopping all over as with the methoxies...

Just fantasizing a little here

 

[dread]

Ok, if we combine all the good parts, we'd come up with:

25C - BCB - NBDHF

or:

 

[PsychedelicPeptide]

Another thing to think about is the role of polypharmacology in eliciting the psychedelic action. According to Ray (Psychedelics and the human receptorome), LSD is active at:

LSD: 4.00 5ht1b, 3.77 5ht7, 3.75 5ht6, 3.73 5ht1a, 3.70 5ht1d,
3.64 5ht5a, 3.54 5ht2a, 3.16 D3, 3.11 5ht2b, 3.11 5ht2c, 2.93
Alpha2A, 2.62 5ht1e, 2.55 D2, 2.39 D4, 2.34 D1, 2.05 D5, 1.54
Alpha1A, 1.40 H1, 1.39 Beta1, 1.05 Beta2, 0.65 Alpha1B;

all these receptors. Now consider how many of these targets are essential for the LSD experience, and how many are not. I personally don't know, 2a is obviously important. But is that entire list really necessary?

If there are ones at the top of the list with no need to be present then we could conceive that a new drug (call it an LSD analog or whatever you want) not having that/those specific action(s) should be more potent by weight because it has less "off-target action." You could extend this into removing say the entire dopamine receptor component which might be a little more feasible than removing affinity for single serotonin receptor isoform. The abundance of each target receptor in the brain is another thing to consider.

Conversely you could travel the other route and try to pack even more polypharmacology into the LSD receptor profile. Say just for the sake of good examples add opiate or cannabinoid receptor affinities to LSD and create some new ultra groovy molecule with even broader receptor activities, but (potentially counter-intuitively) more potent (and novel) action in vivo.

 

[anonymiss]

i found this relevant to this thread

The extension of the two-carbon chain of mescaline by alpha-methylation to the
three carbon chain of TMA approximately doubled the potency of the compound. And it
was felt to be a completely logical possibility that, by extending it one more carbon
atom, to the four carbon chain of alpha-ethyl-mescaline, it might double again. And
following that logical progression, the doubling of potency with each additional carbon
atom, the factor would be 2 to the 7th power by the alpha-octyl (or 256x that of
mescaline, or a milligram as active dose) and with a side chain of a 70-carbon alkyl
group (alpha-heptacontylmescaline) it would take just a single molecule to be
intoxicating. This was rich fantasy stuff. As an active compound, just where would it go
in the brain? With an 80-carbon side-chain, would one-thousandth of a single molecule
be enough for a person? Or might a single molecule intoxicate a thousand people? And
how long a chain on the alpha-position might be sufficient that, by merely writing down
the structure on a piece of paper, you would get high? Maybe just conceiving the
structure in your mind would do it. That is, after all, the way of homeopathy. Maybe it
was just as well that this added two-carbon side-chain with lowered activity was already
enough to disprove the doubling pattern. But by the time this non-activity had been
learned, the alpha series had already been pushed out quite aways

 

[Solipsis]

Inductio ad absurdum?