Psychedelic affinity chart (also: design the perfect one!)

[knockout_mice]

I was always wondering what receptor affinities would a really clean, physical side-effect or bodyload free psychedelic have...

• What 5-HT2A / 5-HT2C affinity ratio is favorable, does it need to have 5HT-1A receptor affinity as well?
• Full or partial agonists?
• Short or long half-life?

Search for affinites here: http://pdsp.cwru.edu/pdsp.php

Examples:

LSD

5-HT_1A: 1.1 nM Ki Nichols DE, et al., 2002
5-HT_2A: 0.76 nM Ki Knight AR, et al., 2004
5-HT_2B: 0.98 nM Ki Knight AR, et al., 2004
5-HT_2C: 1.1 nM Ki Knight AR, et al., 2004

selectivity for 5-HT2A over 5-HT2C: 1.4x

25i-NBOMe

5-HT_1A: >500 nM Ki Nichols DE, et al., 2008
5-HT_2A: 0.044 nM Ki Nichols DE, et al., 2008
5-HT_2B: 231 nM Ki Nichols DE, et al., 2008
5-HT_2C: 2 nM Ki Nichols DE, et al., 2008

selectivity for 5-HT2A over 5-HT2C: 45.4x

I suppose 5-HT1A agonism can counteract the severe vasoconstriction of 5HT2A agonsits, what do you think?

 

[sekio]

Where are you going with this? As far as we know, "body load" does not have any central locus of activity, as evidenced by people complaining of bad trips on super-selective 2a agonists like the NBOMe series.

 

[ebola?]

as evidenced by people complaining of bad trips on super-selective 2a agonists like the NBOMe series

Are these compounds so highly selective beyond 5ht receptors? Have we confirmed that they aren't significantly adrenergic, for example?

ebola

 

[sekio]

I seem to recall that Heim's thesis work detailed the selectivity of the NBOMe series for 5ht2a over a variety of other receptors. (dopamine, opioid, muscarinic etc)

 

[knockout_mice]

Are these compounds so highly selective beyond 5ht receptors? Have we confirmed that they aren't significantly adrenergic, for example?

You can find a nice table for 5HT receptor affinities of NBOMe compounds here: https://docs.google.com/file/d/0BwXelgjm5BeEaEJJU0lPa1NnaGM/edit (page 181)
25i-NBOMe is confirmed to be selective among the other known relevant receptors as well: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2719953/ and https://www.ncbi.nlm.nih.gov/pubmed/21174090

I don't think that it's safe to assume that body load=vasoconstriction

Sounds plausable at first but it seems that 5ht-1a receptor mediated vasodilation is disputed.
Wikipedia cites This study, which demonstrates that 5-HT1A receptor agonists 8-OH-DPAT and flesinoxan have a vasodilatory effect, but it looks like this wasn't down to 5ht-1a activation
http://europepmc.org/abstract/MED/1686254/reload=0;jsessionid=3KlUfScPQASEeXuIYDhN.0
http://onlinelibrary.wiley.com/doi/10.1111/j.1474-8673.1991.tb00321.x/abstract
http://www.ncbi.nlm.nih.gov/pubmed/7528302

Thanks for the info, Toucan!
I don't think that body load = vasoconstriction, but in my experience 25i-NBOMe's only downside is the latter and a little gastric distress (with higher doses the peripheral side-effects are stronger). If not 5-HT1A, then which serotonin receptor mediates vasodilation? 8-OH-DPAT also has 5HT7 agonist and SERT blocker properties.

knockout_mice

 

[Cortexiphan]

Comparing Ki's is a tricky business at best, useless at worst. If the assay is not run against the same radioligand in the same cells using the same conditions, you can get wildly fluctuating values for the same receptor, even when the Cheng Prusoff equation is supposed account for that by factoring in the Kd of the radioligand in the assay.

 

[ebola?]

What 5-HT2A / 5-HT2C affinity ratio is favorable, does it need to have 5HT-1A receptor affinity as well?
Full or partial agonists?
Short or long half-life?

Wouldn't this mainly depend on what kind of effects you're into?

ebola

 

[knockout_mice]

Comparing Ki's is a tricky business at best, useless at worst. If the assay is not run against the same radioligand in the same cells using the same conditions, you can get wildly fluctuating values for the same receptor, even when the Cheng Prusoff equation is supposed account for that by factoring in the Kd of the radioligand in the assay.

I agree. Here, for each ligand I tried to use data from the same source, preferring human cloned tissue.
If the values come from the same source with identical testing conditions, then the Ki/Ki ratios should be consistent as well, am I wrong? And that's something we can use.

knockout_mice

 

[knockout_mice]

Wouldn't this mainly depend on what kind of effects you're into?

ebola

For minimizing the possible risks / toxicity / side-effects with a real clean mental feel.
(Could somebody edit the title and change perfect to 'cleanest'? Thanks!)

knockout_mice

 

[Cortexiphan]

Are these compounds so highly selective beyond 5ht receptors? Have we confirmed that they aren't significantly adrenergic, for example?

ebola

As to that there is a nice table with Ki values in the supplementary material for this paper.
The adrenergic Ki's are generally 100 fold higher or better than the 5-HT2 receptors.

Interestingly, the 5-HT2B Ki for 25I-NBOMe is 100 fold lower than the one reported by Nichols (2.3 nM vs. 231 nM) and both were measured at PDSP.

 

[knockout_mice]

As to that there is a nice table with Ki values in the supplementary material for this paper.
The adrenergic Ki's are generally 100 fold higher or better than the 5-HT2 receptors.

Interestingly, the 5-HT2B Ki for 25I-NBOMe is 100 fold lower than the one reported by Nichols (2.3 nM vs. 231 nM) and both were measured at PDSP.

According to this document Cimbi-21 (25i-NBF) is a much more selective ligand for 5HT2A than 25i-NBOMe?

 

[Cortexiphan]

According to this document Cimbi-21 (25i-NBF) is a much more selective ligand for 5HT2A than 25i-NBOMe?

True, it's also less potent, but again this depends on the assays. It seems to be significantly less potent compared to 25I-NBOMe in rat cells but only slightly so in human cells.

 

[ebola?]

Right. But as far as recreational drugs go, do we really need microgram-potency agents? Compounds with dosage ranges of 10-30 mg are so much easier to prepare for dosing at appropriate levels.

ebola

 

[Hammilton]

To quote Macklemore,

that’s just some ignorant bitch shit
I call that getting swindled and pimped, shit
I call that getting tricked by business

So it sounds better than it reads.

The only one it really benefits is the guy selling it. The smaller a dose unit is, the cheaper it is, the more money you can make. The best psychedelics I've ever had were medium potency (2C-B, 4-HO-DiPT, some of these drugs make psilocybin look medium potency! mescaline would never have been used by anyone if it were up to people with a profit motive to synthesize it. Fortunately nature takes care of that for us.

If anyone hasn't heard/seen this excellent parody of Macklemore's (who makes an appearance) song "Thrift Shop," titled "Pot Shop" by Steve Berke, who recently lost a campaign for mayor of Miami (I think it was miami...) I highly suggest watching it here: http://www.youtube.com/watch?v=Znpt_Umixcs

 

[sekio]

Well, if one were designing a PET ligand, of course you would want ultralow Kis & only need to administer micrograms of (potentially radioactive) compound to your subjects. But I think the core issue here is that the factors that make for a good in-vitro ligand don't neccesarily make for an excellent psychedelic.

Then again, there is something to be said for LSD, why does it remain so popular if it is so potent?

Really I have always thought that there must be something to the "receptor diversity" of small molecule psychedelic drugs playing a part in their perceptual effects. Call me a holist but I don't think many of these drugs can have their effects tied up nicely to one receptor (5ht2a) and all the other activity at other receptors is "bad". A lot of people find compounds liek the NBOMe series very "hollow" but compounds like DMT/mescaline that have comparably low affinity for 5ht2a are valued greatly as complex drugs. Maybe, perhaps, even slight-to-moderate activation of normally "anxiogenic/bad" receptors are responsible for the unique effects of popular psychedelics.

 

[xx001]

Wouldn't it be a bit misleading to simply compare ki values since affinity != activity, necessarily?

 

[sekio]

Yes indeed, but it's a better metric than wild guesses.

 

[ebola?]

Really I have always thought that there must be something to the "receptor diversity" of small molecule psychedelic drugs playing a part in their perceptual effects. Call me a holist but I don't think many of these drugs can have their effects tied up nicely to one receptor (5ht2a) and all the other activity at other receptors is "bad". A lot of people find compounds liek the NBOMe series very "hollow" but compounds like DMT/mescaline that have comparably low affinity for 5ht2a are valued greatly as complex drugs. Maybe, perhaps, even slight-to-moderate activation of normally "anxiogenic/bad" receptors are responsible for the unique effects of popular psychedelics.

Then again, I vastly prefer those 5ht2a selective agents that some find 'bland'. It seems to be a matter of taste, except for some specific activities being very widely rejected.

ebola

 

[psood0nym]

Call me a holist but I don't think many of these drugs can have their effects tied up nicely to one receptor (5ht2a) and all the other activity at other receptors is "bad". A lot of people find compounds liek the NBOMe series very "hollow" but compounds like DMT/mescaline that have comparably low affinity for 5ht2a are valued greatly as complex drugs. Maybe, perhaps, even slight-to-moderate activation of normally "anxiogenic/bad" receptors are responsible for the unique effects of popular psychedelics.

I agree. But I'd even go further and bet the notion that a promiscuous receptor affinity profile makes for a "dirty" experience is fundamentally flawed. I suspect rationalization and confirmation bias account for most of the claims insisting on the predictive validity of such a reductionist model. I'm not well versed in pharmacology, but I don't need to be to be fairly confident in this assertion. All I need to recognize is that the brain is a complex associational network. Small differences in neuronal firing patterns, already complicated at the local level by the interplay of ligand efficacy and affinity, fan out into widely divergent patterns of signal propagation and decay. As it is presumably this network pattern that underlies subjective psychedelic effects, trying to extrapolate from activity at individual nodes to predictions that account for spreading activation within the most complex structure in the known universe is perhaps a bit arrogant (albeit the same logic may not apply to the localized flooding strategy of something like serotonin transporter reversers).

 

[specialspack]

Really I have always thought that there must be something to the "receptor diversity" of small molecule psychedelic drugs playing a part in their perceptual effects. Call me a holist but I don't think many of these drugs can have their effects tied up nicely to one receptor (5ht2a) and all the other activity at other receptors is "bad". A lot of people find compounds liek the NBOMe series very "hollow" but compounds like DMT/mescaline that have comparably low affinity for 5ht2a are valued greatly as complex drugs. Maybe, perhaps, even slight-to-moderate activation of normally "anxiogenic/bad" receptors are responsible for the unique effects of popular psychedelics.

This.

It would be really useful to see more studies in humans with co-administration of ketanserin and psychedelics though.