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

[bloodshed344]

" N-Methyl-N-(3,4,5-dimethoxy)phenylpropyl-5-MeO-tryptamine, and N-Methyl-N-(3-(5-MeO)indolyl)ethyl-5-MeO-tryptamine"

Sorry to keep asking for pictures, but I know the first structure is not correct (says dimethoxy but has 3,4,5) and these two structures seem much different than the others... I'm interested to see what they would look like because they are confounding me The first one is like a mescaline hybrid? and the second one is... just confusing.

Also, does the higher IA% at different uM / nM mean that some of them are much less potent at binding but show a lot more activity when they do? and does it mean some bind really tightly and only give off partial activity?


Also, as an aside where could I look to find a picture of how a psychedelic (phenethylamine and tryptamine as I'm aware they dock differently I'm not sure about LSD) binds to the serotonin receptor? Thanks.

 

[babylonboy]

These things look great. Like, "I like to draw random molecules" super great. Would particularly like to see the thing with a 2,5-dimethoxylated phenyl avec halide groups at the para position, and the 3,4-dimethoxylated guy 3,4,5-trimethoxylated so it was actually a mescaline/DMT conjoined twin.

bloodshed, the first structure is, as you say, incorrect, but the intention is probably to refer to something that looks a lot like the mescaline/DMT Siamese thang to which I referred. The second one is the lovely symmetrical guy that sekio was talking about with dual methoxyl groups attached (or the one below it with another methoxyl).

EDIT: Made you pics 'cos I'm nice. Top one is the first thing you mentioned (plz excuse the unconventional and energetically unlikely geometry I'm lazy and hungover and hey shutup), the second one is the mescaline mekkin lurve to DMT thing that your nonsensical formula probably refers to something like and about which I was also talking, and the last thing is the 4-halogenated analogue that was of interest to me, myself, and I.

btw srsly nuke r u trolling or what? all we need is an MDO bridge on one of these badboys and we'll be in true "hey gaiz idk wtf SAR is but look at my cool new drug it's like super xtc" territory. ok i'm officially too mashed to be posting in this forum will take it to one of the stupider forums kthxbai.

 

[Lightning-Nl]

[...]

I'm trying to understand chemistry a bit better. My understanding of the reason why the top one is making everyone's mouth water is because it's polarity is really high, correct? From what I already know, this means it could easily cross BBB and would have a huge binding affinity for whatever 5HT/DA receptors it binds to right?

 

[babylonboy]

Which top one? In any case, no, we tend not to get too stiff over polar drugs, for a start you've got it backwards, hydrophobic molecules cross the BBB more readily, and the ability of a drug to cross the BBB is not really something that gets people interested so much as things like receptor affinity. Anyhoo, I'm alright at chem, pretty poor on pharmacology, I'm sure someone more into it will explain much better. These things are interesting because they're novel, have affinities for the receptors associated with psychedelic action, are potentially potent and worth exploring recreationally, and also, they're like two independently active psychedelic structures smashed into crazy hybrid forms (which is really the neatest part). Something that looks like mirrored DMT is just a nice idea. They'll also be legal, as an aside. None of these molecules is polar, really, btw- when you see aromatic rings, that means hydrophobicity.

 

[mad_scientist]

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?

Yes there are LSD analogues that are 5HT2 antagonists, LY-215,840 for instance. I would guess NBOMe-2CHx (i.e. N-(2-methoxybenzyl)-2,5-dimethoxy-4-(n-hexyl)phenethylamine) might well be a potent 5HT2A antagonist and probably with better selectivity than DOHx too.

 

[nuke]

" N-Methyl-N-(3,4,5-dimethoxy)phenylpropyl-5-MeO-tryptamine, and N-Methyl-N-(3-(5-MeO)indolyl)ethyl-5-MeO-tryptamine"

Sorry to keep asking for pictures, but I know the first structure is not correct (says dimethoxy but has 3,4,5) and these two structures seem much different than the others... I'm interested to see what they would look like because they are confounding me The first one is like a mescaline hybrid? and the second one is... just confusing.

Also, does the higher IA% at different uM / nM mean that some of them are much less potent at binding but show a lot more activity when they do? and does it mean some bind really tightly and only give off partial activity?


Also, as an aside where could I look to find a picture of how a psychedelic (phenethylamine and tryptamine as I'm aware they dock differently I'm not sure about LSD) binds to the serotonin receptor? Thanks.

Yeah, the first name should be: N-Methyl-N-(3,4,5-trimethoxy)phenylpropyl-5-MeO-tryptamine

The second one looks kind of like a dimer of 5-MeO-NMT

The answer to the intrinsic activity question is: Yes, and yes.

All agonists and partial agonists have IA curves, eg

If it's a full agonist you'll hit 100% or close to at some concentration, while a partial agonist maxes out at less than.

The drugs potency is how far shifted/scaled to the left or right this curve is. More potent drugs have curves farther to the left, while less potent curves are farther to the right. The IA% I listed are simply a single point on this curve.

Crystal structures of the 5HT receptors with bound ligands were published earlier this year:
http://pdb.org/pdb/101/motm.do?momID=164
http://pdb.org/pdb/explore/explore.do?structureId=4IB4
http://pdb.org/pdb/explore/explore.do?structureId=4IAR
http://pdb.org/pdb/explore/explore.do?structureId=4IAQ
http://pdb.org/pdb/explore/explore.do?structureId=2YME
http://pdb.org/pdb/explore/explore.do?structureId=2YMD

 

[nuke]

These things look great. Like, "I like to draw random molecules" super great. Would particularly like to see the thing with a 2,5-dimethoxylated phenyl avec halide groups at the para position, and the 3,4-dimethoxylated guy 3,4,5-trimethoxylated so it was actually a mescaline/DMT conjoined twin.

bloodshed, the first structure is, as you say, incorrect, but the intention is probably to refer to something that looks a lot like the mescaline/DMT Siamese thang to which I referred. The second one is the lovely symmetrical guy that sekio was talking about with dual methoxyl groups attached (or the one below it with another methoxyl).

EDIT: Made you pics 'cos I'm nice. Top one is the first thing you mentioned (plz excuse the unconventional and energetically unlikely geometry I'm lazy and hungover and hey shutup), the second one is the mescaline mekkin lurve to DMT thing that your nonsensical formula probably refers to something like and about which I was also talking, and the last thing is the 4-halogenated analogue that was of interest to me, myself, and I.

btw srsly nuke r u trolling or what? all we need is an MDO bridge on one of these badboys and we'll be in true "hey gaiz idk wtf SAR is but look at my cool new drug it's like super xtc" territory. ok i'm officially too mashed to be posting in this forum will take it to one of the stupider forums kthxbai.

The 3,4,5-Trimethoxy derivative you drew is close, but has a propylene rather than an ethylene bridge (N-Methyl-N-(3,4,5-trimethoxy)phenylpropyl-5-MeO-tryptamine)

 

[babylonboy]

Right you are, guess I just had mescaline on the brain. If I was being defensive I'd say I was trying to make sense of an inconsistent formula, but yeah, I just didn't read it properly.

 

[bloodshed344]

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...

That's not a tryptamine though, that's a nitrobenzimidazole... who knows if it would be psychedelic if you replaced the rest of the molecule. It does seem similar however.