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Wacky, potentially psychedelic ultrapotent hybrid compounds from Jensen Ph.D. Thesis

nuke

nuke

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"Yo dawg, I heard you like phenethylamines, so I put some phenethylamines on your tryptamines so you can trip while you trip!"

Ph.D. Thesis is entitled, "Tryptamines as Ligands and Modulators of the Serotonin 5-HT2A Receptor and the Isolation of Aeruginascin from the Hallucinogenic Mushroom Inocybe aeruginascens." By Niels Jensen, from die Georg-August-Universität zu Göttingen.

There are some interesting 5HT2A agonists reported, aside from a vast array of 5HT2A antagonists. Activity (EC50/IA) is measured from PI turnover. I'll just report the ones that show at least partial agonist activity below 1 uM. I haven't seen this thesis discussed often, so I thought I'd throw out this data for everyone.

IA = Intrinsic activity

5-Unsubstituted Tryptamine 5HT2A Partial Agonists
REFERENCE: DMT 41% IA at 2239 nM

N-Methyl-N-(2,5-dimethyl)phenylethyltryptamine 26% IA at 235 nM, 112% IA at 32 uM
N-Methyl-N-(3,5-dimethyl)phenylethyltryptamine 41% IA at 281 nM, 86% IA at 10 uM, 164% IA at 32 uM
N-Methyl-N-(2,5-dimethoxy)phenylethyltryptamine 19% IA at 18 nM, 37% IA at 10 uM
N-Methyl-N-(3-acetoxy)phenylethyltryptamine 38% IA at 98 nM, 57% IA at 10 uM, 92% IA at 32 uM
N-Methyl-N-(3,4-dimethoxy)phenylethyltryptamine 34% IA at 44 nM, 42% IA at 10 uM
N-Methyl-N-(3-methoxy)phenylethyltryptamine 28% IA at 324 nM, 43% IA at 10 uM, 92% IA at 32 uM
N-Methyl-N-(3-indolyl)ethyltryptamine 25% IA at 132 nM, 30% IA at 10 uM, 54% IA at 32 uM
N-Methyl-N-(3-(5-MeO)indolyl)ethyltryptamine 24% IA at 50 nM, 30% IA at 10 uM, 54% IA at 32 uM
N-Methyl-N-1-naphthyltryptamine 26% IA at 290 nM, 64% IA at 10 uM, 94% IA at 32 uM

5-Methoxylated Tryptamine 5HT2A Partial Agonists
REFERENCE: 5-MeO-DMT 98% IA at 741 nM

N-Methyl-N-(2,5-dimethyl)phenylethyl-5-MeO-tryptamine 34% IA at 309 nM
N-Methyl-N-(2,5-dimethoxy)phenylethyl-5-MeO-tryptamine 27% IA at 320 nM, 31% IA at 10 uM, 47% IA at 32 uM
N-Methyl-N-(3,4-dimethoxy)phenylethyl-5-MeO-tryptamine 62% IA at 84 nM, 75% IA at 10 uM
N-Methyl-N-(4-methoxy)phenylethyl-5-MeO-tryptamine 40% IA at 302 nM, 27% IA at 1 uM (what? bimodal?), 42% IA at 10 uM
N-Methyl-N-(3-indolyl)ethyl-5-MeO-tryptamine 24% IA at 50 nM, 30% IA at 10 uM, 54% IA at 32 uM
N-Methyl-N-(3-(5-MeO)indolyl)ethyl-5-MeO-tryptamine 64% IA at 87 nM, 79% IA at 32 uM
N-Methyl-N-1-naphthyl-5-MeO-tryptamine 14% IA at 182 nM, 46% IA at 10 uM
N-Methyl-N-(3,4,5-dimethoxy)phenylpropyl-5-MeO-tryptamine 47% IA at 257 nM, 57% IA at 32 uM
N-Methyl-N-allyl-5-MeO-tryptamine 92% IA at 575 nM
N-Methyl-N-propynyl-5-MeO-tryptamine 81% IA at 811 nM, 93% IA at 32 uM

Other notable stuff:
- The 5-MeO-T derivatives appear to lose their crazy affinity for 5HT1A as compared to 5HT2A (5-MeO-DMT is almost 5 fold more selective for 5HT1A as compared to DMT), except for N-Methyl-N-(3,4,5-dimethoxy)phenylpropyl-5-MeO-tryptamine, N-Methyl-N-allyl-5-MeO-tryptamine, and N-Methyl-N-(3-(5-MeO)indolyl)ethyl-5-MeO-tryptamine. I will conjecture that they're probably more subjectively DMT or 4-HO-DMT like if they are active, but who knows.
- The 5-Unsubstituted tryptamine derivatives completely lose selectivity for 5HT1A over 5HT2A, with an order of magnitude or more loss in 5HT1A:5HT2A Ki ratio
- Both the 5-MeO-T derivatives and the 5-unsubstituted tryptamine derivatives tend to have smaller 5HT2A:5HT2C binding ratios as compared to their reference N,N-dimethylated psychedelics; the significance of this is unknown
 
nuke said:
"Yo dawg, I heard you like phenethylamines, so I put some phenethylamines on your tryptamines so you can trip while you trip!"

Ph.D. Thesis is entitled, "Tryptamines as Ligands and Modulators of the Serotonin 5-HT2A Receptor and the Isolation of Aeruginascin from the Hallucinogenic Mushroom Inocybe aeruginascens." By Niels Jensen, from die Georg-August-Universität zu Göttingen.

There are some interesting 5HT2A agonists reported, aside from a vast array of 5HT2A antagonists. Activity (EC50/IA) is measured from PI turnover. I'll just report the ones that show at least partial agonist activity below 1 uM. I haven't seen this thesis discussed often, so I thought I'd throw out this data for everyone.

IA = Intrinsic activity

5-Unsubstituted Tryptamine 5HT2A Partial Agonists
REFERENCE: DMT 41% IA at 2239 nM

N-Methyl-N-(2,5-dimethyl)phenylethyltryptamine 26% IA at 235 nM, 112% IA at 32 uM
N-Methyl-N-(3,5-dimethyl)phenylethyltryptamine 41% IA at 281 nM, 86% IA at 10 uM, 164% IA at 32 uM
N-Methyl-N-(2,5-dimethoxy)phenylethyltryptamine 19% IA at 18 nM, 37% IA at 10 uM
N-Methyl-N-(3-acetoxy)phenylethyltryptamine 38% IA at 98 nM, 57% IA at 10 uM, 92% IA at 32 uM
N-Methyl-N-(3,4-dimethoxy)phenylethyltryptamine 34% IA at 44 nM, 42% IA at 10 uM
N-Methyl-N-(3-methoxy)phenylethyltryptamine 28% IA at 324 nM, 43% IA at 10 uM, 92% IA at 32 uM
N-Methyl-N-(3-indolyl)ethyltryptamine 25% IA at 132 nM, 30% IA at 10 uM, 54% IA at 32 uM
N-Methyl-N-(3-(5-MeO)indolyl)ethyltryptamine 24% IA at 50 nM, 30% IA at 10 uM, 54% IA at 32 uM
N-Methyl-N-1-naphthyltryptamine 26% IA at 290 nM, 64% IA at 10 uM, 94% IA at 32 uM

5-Methoxylated Tryptamine 5HT2A Partial Agonists
REFERENCE: 5-MeO-DMT 98% IA at 741 nM

N-Methyl-N-(2,5-dimethyl)phenylethyl-5-MeO-tryptamine 34% IA at 309 nM
N-Methyl-N-(2,5-dimethoxy)phenylethyl-5-MeO-tryptamine 27% IA at 320 nM, 31% IA at 10 uM, 47% IA at 32 uM
N-Methyl-N-(3,4-dimethoxy)phenylethyl-5-MeO-tryptamine 62% IA at 84 nM, 75% IA at 10 uM
N-Methyl-N-(4-methoxy)phenylethyl-5-MeO-tryptamine 40% IA at 302 nM, 27% IA at 1 uM (what? bimodal?), 42% IA at 10 uM
N-Methyl-N-(3-indolyl)ethyl-5-MeO-tryptamine 24% IA at 50 nM, 30% IA at 10 uM, 54% IA at 32 uM
N-Methyl-N-(3-(5-MeO)indolyl)ethyl-5-MeO-tryptamine 64% IA at 87 nM, 79% IA at 32 uM
N-Methyl-N-1-naphthyl-5-MeO-tryptamine 14% IA at 182 nM, 46% IA at 10 uM
N-Methyl-N-(3,4,5-dimethoxy)phenylpropyl-5-MeO-tryptamine 47% IA at 257 nM, 57% IA at 32 uM
N-Methyl-N-allyl-5-MeO-tryptamine 92% IA at 575 nM
N-Methyl-N-propynyl-5-MeO-tryptamine 81% IA at 811 nM, 93% IA at 32 uM

Other notable stuff:
- The 5-MeO-T derivatives appear to lose their crazy affinity for 5HT1A as compared to 5HT2A (5-MeO-DMT is almost 5 fold more selective for 5HT1A as compared to DMT), except for N-Methyl-N-(3,4,5-dimethoxy)phenylpropyl-5-MeO-tryptamine, N-Methyl-N-allyl-5-MeO-tryptamine, and N-Methyl-N-(3-(5-MeO)indolyl)ethyl-5-MeO-tryptamine. I will conjecture that they're probably more subjectively DMT or 4-HO-DMT like if they are active, but who knows.
- The 5-Unsubstituted tryptamine derivatives completely lose selectivity for 5HT1A over 5HT2A, with an order of magnitude or more loss in 5HT1A:5HT2A Ki ratio
- Both the 5-MeO-T derivatives and the 5-unsubstituted tryptamine derivatives tend to have smaller 5HT2A:5HT2C binding ratios as compared to their reference N,N-dimethylated psychedelics; the significance of this is unknown
Click to expand...

I want some pictures! Seriously, very interesting stuff. and also I thought of 5-meo/4-ho-MALT myself.
 
I certainly had the N-Methyl-N-(3,4-dimethoxy)phenylethyl-5-MeO-tryptamine on my list of compounds to return to in future when the opportunity arose...however I had dismissed most of these as being too weak partial agonists at 5HT2A, figured they would just make you feel weird but not trip out properly.

I did not realise that DMT itself only has an efficacy of 41% in the same assay, that changes things completely! Looks like the compounds you have highlighted have a good chance of showing activity similar to their relatives in TiHKAL. I like the look of this one too, N-Methyl-N-(3-(5-MeO)indolyl)ethyl-5-MeO-tryptamine as that symmetry is beautiful, probably easy to make too...
 
mad_scientist said:
I certainly had the N-Methyl-N-(3,4-dimethoxy)phenylethyl-5-MeO-tryptamine on my list of compounds to return to in future when the opportunity arose...however I had dismissed most of these as being too weak partial agonists at 5HT2A, figured they would just make you feel weird but not trip out properly.

I did not realise that DMT itself only has an efficacy of 41% in the same assay, that changes things completely! Looks like the compounds you have highlighted have a good chance of showing activity similar to their relatives in TiHKAL. I like the look of this one too, N-Methyl-N-(3-(5-MeO)indolyl)ethyl-5-MeO-tryptamine as that symmetry is beautiful, probably easy to make too...
Click to expand...
I bet there are some real gems in here, think DMT and LSD. Also, I bet there's some like 5-MeO-MiPT that are useful in different senses, or maybe some that aren't very psychedelic at all while giving desired body and mind effects for a more recreation/entheogenic experience. Then think, there could alpha-methyl versions of these chemicals with vastly different pharmacology (I wouldn't be surprised if some were increased in potency such as the phenylindol compounds and some that were pretty much inactive)

A new treasure trove, also that Diethylamide phenethylamine molecule in another thread is really interesting... I have more faith in psychedelic analogs than ever! Bring on the alphabet soup.

Also, would some chemically minded person please do a basic sketch of the skeletons of those phenylindols and (maybe) the others too? :D
 
mad_scientist said:
I certainly had the N-Methyl-N-(3,4-dimethoxy)phenylethyl-5-MeO-tryptamine on my list of compounds to return to in future when the opportunity arose...however I had dismissed most of these as being too weak partial agonists at 5HT2A, figured they would just make you feel weird but not trip out properly.

I did not realise that DMT itself only has an efficacy of 41% in the same assay, that changes things completely! Looks like the compounds you have highlighted have a good chance of showing activity similar to their relatives in TiHKAL. I like the look of this one too, N-Methyl-N-(3-(5-MeO)indolyl)ethyl-5-MeO-tryptamine as that symmetry is beautiful, probably easy to make too...
Click to expand...

The NBOMe compounds have around 40% efficacy too and are extremely active (if not occasionally deadly). The EC50 of LSD at 5HT2A is ~7-8 nM (depending on the assay conditions) and has an intrinsic activity of only 22% in terms of IP3 turnover. I think it's likely that the safest psychedelics will have ~20% IA at 5HT2A receptors. By the looks of it above, the most potent compound, N-Methyl-N-(2,5-dimethoxy)phenylethyltryptamine, may be active in the sub-milligram range, although I have no idea how well absorbed it would be.
 
I do not think aeruginescin is even remotely suitable for bioassay.

It is a quite potent 5HT3 agonist, and as such, I would think it likely to cause a pukefest and horrendous nausea.
 
bloodshed344 said:
Also, would some chemically minded person please do a basic sketch of the skeletons of those phenylindols and (maybe) the others too? :D
Click to expand...
I would if this site still let you attach pictures to posts 8(

here is a PubChem link for N-(3,4-dimethoxy)phenylethyltryptamine which should give you an idea of the kind of structures we are talking about here, the others are similar but with N-methyl added, and varying substitutions on the phenethyl portion.

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3750667
 
I would if this site still let you attach pictures to posts
Click to expand...

I'd just link to imgur or something. Also, great to see you kicking around here! :)

ebola
 
mad_scientist said:
I would if this site still let you attach pictures to posts 8(

here is a PubChem link for N-(3,4-dimethoxy)phenylethyltryptamine which should give you an idea of the kind of structures we are talking about here, the others are similar but with N-methyl added, and varying substitutions on the phenethyl portion.

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3750667
Click to expand...

Wow, thanks a lot! I had googled some of these and couldn't find a thing. That picture though... that's one ugly molecule. Hope it feels better than it looks.

Also the molecules in OP say N-methyl as well, does that mean these also have a methyl at the N unlike the one you showed me?
 
bloodshed344 said:
Wow, thanks a lot! I had googled some of these and couldn't find a thing. That picture though... that's one ugly molecule. Hope it feels better than it looks.

Also the molecules in OP say N-methyl as well, does that mean these also have a methyl at the N unlike the one you showed me?
Click to expand...

IsomerDesign kindly uploaded them all;

pk5607.png

N-Methyl-N-(2,5-dimethyl)phenylethyltryptamine

pk5616.png

N-Methyl-N-(3,5-dimethyl)phenylethyltryptamine

pk5609.png

N-Methyl-N-(2,5-dimethoxy)phenylethyltryptamine

pk5612.png

N-Methyl-N-(3-acetoxy)phenylethyltryptamine

pk5617.png

N-Methyl-N-(3,4-dimethoxy)phenylethyltryptamine

pk5613.png

N-Methyl-N-(3-methoxy)phenylethyltryptamine

pk5626.png

N-Methyl-N-(3-indolyl)ethyltryptamine

pk5627.png

N-Methyl-N-(3-(5-MeO)indolyl)ethyltryptamine

pk5628.png

N-Methyl-N-1-naphthyltryptamine

The 5-MeO-derivatives are obviously the same, just 5-methoxylated.
 
N-Methyl-N-(3-indolyl)ethyltryptamine

This one smells like it's a natural product, somewhere.... (or a product of botched dmt synthesis). What a lovely symmetry.
 
It's interesting to me because my understanding (please correct me of I'm wrong) is that N-benzyl tryptamines like /5-MeO-NBpBrT exhibit antagonistic activity. Hence their not being produced to complement the phenethylamine NBOMes. I wonder if the extra N-methyl and resulting tertiary amine or the two-carbon spacer instead of just a single carbon shifts the activity to agonist/partial-agonist. That two-carbon spacer also shows up in the putative agonist/partial-agonist (not specified in the paper) with high binding affinity (~3 nM) that I posted about here in ADD with a diethylamide moiety instead of a phenyl-whatever as in these compounds after the two-carbon spacer.

Anybody care to speculate as to why these appear to be different in their effect once bound compared to the 'tryptamine NBOMes'?

I also wonder about that N-methyl as mentioned above. Besides any possible function in producing agonistic instead of antagonistic activity, I wonder if it may be stripped off in the liver. Ergoloids can apparently lose a methyl from the indolic nitrogen, but I don't know whether this applies primarily to ergoloids or whether this is broadly applicable to any tertiary amine. If it does, and these compounds were to turn out to be good psychedelics, I would wonder about that demethylated secondary amine metabolite as far as possibly also being active. Any thoughts?
 
Last edited:
Deinonychus said:
It's interesting to me because my understanding (please correct me of I'm wrong) is that N-benzyl tryptamines like /5-MeO-NBpBrT exhibit antagonistic activity. Hence their not being produced to complement the phenethylamine NBOMes. I wonder if the extra N-methyl and resulting tertiary amine or the two-carbon spacer instead of just a single carbon shifts the activity to agonist/partial-agonist. That two-carbon spacer also shows up in the putative agonist/partial-agonist (not specified in the paper) with high binding affinity (~3 nM) that I posted about here in ADD with a diethylamide moiety instead of a phenyl-whatever as in these compounds after the two-carbon spacer.

Anybody care to speculate as to why these appear to be different in their effect once bound compared to the 'tryptamine NBOMes'?
Click to expand...

I bet some phenethylamine-nbomes are antagonists, besides the well-known ones. I bet it's just a matter of small difference between a powerful agonist and a powerful antagonist. An interesting question would be, are there are any LSD analogs that are strong antagonists?
 
I wonder what these subjectively feel like! Weird how you can just... attach two DMTs together like that or DMT to a 2,5-DMPEA and apparently get something active.
 
Huh, I actually had a theory last night while looking at Etonitazene, what if you kept the tryptamine structure and instead added a 2-ethylphenyl group onto it? As with Etonitazene, adding a para substitution (to the new phenyl ring) would increase potency in varying levels but if you started doing all these kinds of PEA additions too...
 
nuke said:
The NBOMe compounds have around 40% efficacy too and are extremely active (if not occasionally deadly).
Click to expand...

Where's that from? Ettrup et al (2011) and Braden et al (2006) say 83-99% and 78% respectively, at single-digit nM.


Ettrup, A., Hansen, M., Santini, M. a, Paine, J., Gillings, N., Palner, M., … Knudsen, G. M. (2011). Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT (2A) agonist PET tracers. European journal of nuclear medicine and molecular imaging, 38 (4), 681–93. doi:10.1007/s00259-010-1686-8

Braden, M. R., Parrish, J. C., Naylor, J. C., & Nichols, D. E. (2006). Molecular interaction of serotonin 5-HT2A receptor residues Phe339(6.51) and Phe340(6.52) with superpotent N-benzyl phenethylamine agonists. Molecular pharmacology, 70(6), 1956–64. doi:10.1124/mol.106.028720
 
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