7-substituted-tryptamine & B-dragonfly

[Reminisant B]

Does anyone think Shulgin might have already tested 7-subst-tryptamines or Tryp2c/3c compounds?

5-Meo-dalt/dalt information was only released to the public when one research chemical supplier decided to start selling it & he has got his up and coming new book(s) whenever they are to be released.

Not that I would want to force any information out prematurely but wouldn't that be cool if F&B & Advanced Drug discussion have figured out a whole new series of compounds already being investigated! :D

Yes I'm an optimist (well not always)

 

[hugo24]

...or better,eat some 7-Halo-(5-methoxi)-Tryptamines and report effects here!

-(Whats the value of DMT ?) And is there a somewhat similar order: 2,5-Dimethoxi-4-hydroxiphen < 2,4,5-Trimethoxiphen < 2,5-dimethoxi-4-halo,methylphen ?

 

[Morninggloryseed]

Do you have a copy of the paper I can have? Does anyone?

Look what I found ... just as I suspected!

Indolealkylamine analogs share 5-HT2 binding characteristics with phenylalkylamine hallucinogens. Lyon RA, Titeler M, Seggel MR, Glennon RA. Eur J Pharmacol. 1988 Jan 19;145(3):291-7.

Twenty-one indolealkylamines, some of which are known to be psychoactive in man, were examined for their binding interactions with rat brain cortical 5-HT2 receptors labeled with the antagonist radioligand [3H]ketanserin in order to develop structure-activity relationships for binding at these sites. Features investigated included aromatic, alpha-methyl and terminal amine substituents. 4-Methoxy and 5-methoxy substitution impart a higher affinity than 6- or 7-methoxy substitution; a 7-hydroxyl group essentially abolishes affinity whereas a 7-methyl or 7-bromo group enhances affinity. alpha-Methylation has little effect on affinity and, in the one case examined, the S(+) isomer of alpha-methyltryptamine was essentially equipotent with its racemate and twice as potent as its R(-) enantiomer. Terminal amine methylation results in a small but progressive decrease in affinity in the order: primary amine greater than dimethylamine greater than diethylamine. Similarities were noted between these structural requirements for binding and those of the phenalkylamines. Selected compounds (5-methoxytryptamine, N,N-dimethyltryptamine, 5-methoxy-N,N-diethyltryptamine and 5-methoxy-N,N-dimethyltryptamine) were further examined by two-site analysis of displacement studies for [3H]ketanserin specific binding. Hill coefficients were significantly less than unity and computer-assisted analysis indicated that a two-site model better fit the data than a one-site model. In displacement studies using the putative agonist radioligand [3H]DOB to label 5-HT2 receptors affinities were 10-100-fold higher than those using [3H]ketanserin. These results are also consistent with earlier findings using psychoactive phenalkylamines in competition studies for radiolabelled 5-HT2 receptors.

PMID: 3350047 [PubMed - indexed for MEDLINE]

DMT,7-Br
5-HT2A Ki (nM): 170.0

DMT, 7-MeO
5-HT2A Ki (nM): 5,400.0

DMT, 7-OH
5-HT2A Ki (nM): >10,000.0

DMT, 5-MeO,7-Me
5-HT2A Ki (nM): 360.00
Hot ligand: 3H-KETANSERIN

 

[dorothyperkins]

http://download.yousendit.com/B0F70C9E73474325

Sorry, couldnt see how to attach it, am i being a dumbass?

edit: just had a quick look and noticed it says in table 2, if i understand it right, that racemic AMT is a more potent agonist than either enantiomer? Which is the more active enantiomer anyway, i thought it was in tihkal but it seems not. Thought Shulgin would have jumped on that like with DOB/DOM and MDMA in pihkal.

Also the 1-TMT looks potent, anyone know anything about it?

 

[Morninggloryseed]

the isomers of a-MT follow a similar pattern to MDMA....ie opposite of the PEAs.....(+)-a-MT is the more potent isomer....however, if you compare the structures of (+)-a-MT with d-LSD, (-)-DOM, etc....they overlays perfectly...hydrogens oriented the same way.....further confirming (in my mind) that there is a great overlay between the structure/activity relationship between PEAs and indolethylamines. Is what I am saying making sense? I lack the chemistry vernacular to properly articulate my thoughts.

 

[nuke]

Something too that's bothered me, Shulgin only ever made n-methylated amphetamines in PiHKAL. There are no actual n-methylated phenethylamines EG n-methyl-2C-B. It makes me wonder if the methylation of these chemicals might yield something more active.

The n-methyl version of 2c-h was down in affinity from 2c-h itself (Nichols, 2006), but then again, DMT is only about 1/3 as potent a 5HT2A agonist as serotonin itself.

 

[Reminisant B]

^Wasn't N-Ethyl-2C-B floating around @some point. Was mean't to be 2c-b like with more side effects.

 

[LuxEtVeritas]

I do not think N-alkylations make those compounds significantly more active to any notable degree

perhaps by a small degree

ethylation or larger groups may create a somewhat greater duration of activity

 

[nuke]

From another forum:

N-Ethyl-2C-B is almost exactly like 2C-B. If you like 2c-b you won't be dissapointed. I think it's kind of crappy, but i don't like any of the old dirty 2c-x substances.

I dunno though, it was from that Swedish site that's notorious for bullshitting.

 

[Reminisant B]

Well I read a thread on another forum where the user posted information claiming not to have aquired it from that particular source. I am fairly sure I know the one your talking about to which they made clear it wasn't from there.

How reliable this information is though, it is the internet.

 

[nuke]

Yeah. Still, it's a whole new can of worms opened. It would be sad that Shulgin spent so much time on all those n-substituted MD-amphetamine compounds to find nothing when active phenethylamines could've been right around the corner!

edit:

Narration: Meanwhile, Sasha’s been having some success in his search for new mind-altering substances. Mescaline is the well-known active ingredient in cactus; he thinks he’s found another … n methyl mescaline.

Dr Alexander “Sasha” Shulgin: It’s been synthesised many years ago, but it’s never been tried by man. I know no medical or experimental testing with it. It’s a simple compound to make. So I’m going to make the compound and see if it’s active.

http://www.abc.net.au/catalyst/stories/s953876.htm

I guess he must've figured this out at some point, too!

 

[Reminisant B]

what about alpha-methoxy-tryptamines. Deviating from the magical 5,7-tryps but would kind of fit the profile of 4-ho-dmt if viewed ala lsd/bromodragonfly view.

 

[kidamnesiac]

^neat

did the MDMPEA ever get made?

 

[Morninggloryseed]

I think it is too early to say that the 5,7-substitution patter is 'magic' since there are no reports of human activity. Receptor affinity doesn't nessessarly mean anything as many tryptamines and PEAs have similar agonist action to psychedelics...but no CNS effects....like 5-MeO-T, and beta-HO-DOB, etc.

what about alpha-methoxy-tryptamines. Deviating from the magical 5,7-tryps but would kind of fit the profile of 4-ho-dmt if viewed ala lsd/bromodragonfly view.

Here is a pic illustrating what I mean. All three structures can be overlaid on each other, and the H around DOM's a-Me, AMT's a-me, and LSD's stereo center all face the same way.

the isomers of a-MT follow a similar pattern to MDMA....ie opposite of the PEAs.....(+)-a-MT is the more potent isomer....however, if you compare the structures of (+)-a-MT with d-LSD, (-)-DOM, etc....they overlays perfectly...hydrogens oriented the same way.....further confirming (in my mind) that there is a great overlay between the structure/activity relationship between PEAs and indolethylamines. Is what I am saying making sense? I lack the chemistry vernacular to properly articulate my thoughts.

 

[nuke]

hat about alpha-methoxy-tryptamines. Deviating from the magical 5,7-tryps but would kind of fit the profile of 4-ho-dmt if viewed ala lsd/bromodragonfly view

the problem with that is the free rotation around the alpha carbon... the methoxy group will be all over the other side of the molecule too.

I was just bumping through tihkal, which contains refs for the synthesis of the following compounds:
7-Fl-T
7-Cl-T
7-Br-T
7-Me-T
7-Et-T
7-Br-T
7-Br-DMT
7-MeS-T

7-methyl-a-methyl-T
7-propyl-a-methyl-T
7-pentyl-a-methyl-T
7-chloro-a-methyl-T

7-methyl-a-ethyl-T
7-chloro-a-ethyl-T

5-methoxy-7-methyl-T
5-methoxy-7-methyl-DMT
5,7-dimethoxy-T
5,7-dimethoxy-DMT
5-methoxy-7-chloro-T

5,7-dimethoxy-AMT

5,6,7-trimethoxy-T
5,6,7-trimethoxy-DMT

 

[hugo24]

what about alpha-methoxy-tryptamines. Deviating from the magical 5,7-tryps but would kind of fit the profile of 4-ho-dmt if viewed ala lsd/bromodragonfly view.

Unfortunately these kind of aminols are quite unstable.

 

[Reminisant B]

I was just bumping through tihkal, which contains refs for the synthesis of the following compounds:
7-Fl-T
7-Cl-T
7-Br-T
7-Me-T
7-Et-T
7-Br-T
7-Br-DMT
7-MeS-T

7-methyl-a-methyl-T
7-propyl-a-methyl-T
7-pentyl-a-methyl-T
7-chloro-a-methyl-T

7-methyl-a-ethyl-T
7-chloro-a-ethyl-T

5-methoxy-7-methyl-T
5-methoxy-7-methyl-DMT
5,7-dimethoxy-T
5,7-dimethoxy-DMT
5-methoxy-7-chloro-T

5,7-dimethoxy-AMT

5,6,7-trimethoxy-T
5,6,7-trimethoxy-DMT

Does TIHKAL mention all those? Didn't see those. Interesting.

As for the alpha-methoxy-T, agreed I think I was getting SAR fever and getting bit overexcited.

True also we shouldn't refer to 5,7-subst-tryptamines as magic yet, it's all just speculation, although I can maybe be excused within the confines of this thread. :D

 

[Dondante]

Anyone looked at this paper? They use many of the compounds from the Lyon/Glennon paper to construct a QSAR.

Quasi-atomistic Receptor Surrogates for the 5-HT2A Receptor: A 3D-QSAR Study on Hallucinogenic Substances. Meike Schulze-Alexandru, Karl-Artur Kovar, Angelo Vedani

The 5-HT2A receptor is known to act as the biological target for a series of hallucinogenic substances including substituted phenylalkylamines, tryptamines and LSD. A prerequisite for a hallucinogenic effect is an agonistic binding mode to the high-affinity state of the receptor. Attempts to establish a quantitative structure-activity relationship for such compounds are typically based on homology models or 3D-QSAR.

In this paper, we describe a surrogate for the 5-HT2A receptor derived by means of quasi-atomistic receptor modeling (software Quasar), a more recently developed 3D-QSAR technique. This approach allows for the simulation of local induced fit, H-bond flip-flop, and solvation phenomena. The QSARs are established based on a family of receptor-surface models, generated by a genetic algorithm combined with cross-validation. The surrogate for the 5-HT2A receptor yielded a cross-validated q2 of 0.954 for the 23 compounds defining the training set. A series of 7 test compounds was then used to validate the model, resulting in a RMS deviation of 0.40 kcal/mol between G0prd. and G0exp.. The largest individual deviation was 0.61 kcal/ mol, corresponding to an uncertainty of a factor 2.7 in the binding affinity. A scramble test with negative outcome (q2=0.144, slope=-0.019) demonstrates the sensitivity of the model with respect to the biological data. Subsequently, the surrogate was used to estimate the activity of a series of 53 hypothetical congeneric compounds, some of which are predicted to be close in activity to LSD.

The relative alignment of substituted derivatives of both
tryptamines and phenylalkylamines is often discussed controversially
(see, e.g., refs. 14, 25, 32, 53, 54). In our
primordial pharmacophore model, the aromatic ring systems
were oriented analogously to a previous study in our laboratory
[25] and in agreement with other 3D-QSAR simulations
[14, 32, 54]. As the ammonium functionality has been shown
to engage in a strong salt bridge with an aspartate residue at
the true biological receptor [55], we selected a more stringent
alignment protocol (cf. above), where special emphasis was
put on the spatial orientation of the >N-H!H-bond donor.
This was accomplished by means of a vector-alignment
concept (H-extension and lone-pair vectors associated with
ideal H-bond geometries; for details, see ref. 50). Comparison
of these vectors and the electrostatic ®eld exerted by the
ligand molecules suggests thatÐin spite of the structural
differenceÐphenylalkylamines, tryptamines, and ergolines
might well bind to the same receptor site displaying a similar
topology. Such a protocol has been referred to as receptor
mediated alignment [38]. The ligand superposition is shown
in Figure 2.

There seems to be quite a bit more information out there than I'd expected.

 

[vecktor]

^^ they are in the index/ cross reference bit at the back.
If I get time I'll see how many of the referred literature articles are obtainable and or interesting.
V

 

[dorothyperkins]

Morninggloryseed, thanks for the pic, saved me having to do it! Yeah theres obviously some relationship. Why do you think N-substitution seems to help with tryptamines but kills activity in phens? I guess its needed with simple trypts to stop metabolism, or maybe more likely to make it less polar so it can get into the brain?

But with AMT, addition of a methyl group to the nitrogen reduces activity, according to tihkal, i assume alpha,N,N-TMT is even less potent. What about nor-LSD?

Thinking about LSD, if the a-Me of AMT was cyclised onto the 4-position of the indole (or onto the 6-position of DOM), this would lock the amine into what has to be the active conformation. Nichols made some similar analogs of 2cb but with the beta-carbon cyclised onto the ring and it wasnt a much stronger agonist, but it didnt put the amine in the same position as LSD.

Would also be interesting to see some DOM/LSD hybrid, by adding the CHCH(CONR2)CH2 bit across the propylamine side chain, should be quite easy to make from beta-keto DOM.

Dodante, you have a ref for that paper?