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crazy structure variations for the 5-HT receptors

E

EN21

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Nov 17, 2005
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Hi, folks!
Here are some structural variations that try to fuse the tryptamine world with the PEAs by chain relocation (4,5,6,7)
Compound 1, a nor gramine, lacking alkyl chains on the nitrogen and a two carbon distance from the benzene moiety to the amine could in theory also be rather active, than normal gramine.
Although 2 might be relatively hydrophilic, it might have a better chance to hit the receptor with the right groups.
Hydroxylamine derivatives similar to 3 are described as CNS acting substances in a patent from 1965.

Totally stupid or probably any good idea?
 
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Using the idea that to show any great degree of activity the compound(s) need to roughly fit the structure of D-LSD/serotonin in terms of bond length, stereochemistry and lone pair electron orientation for formation of hydrogen bonds.

Out of the structures shown, 2 is effectively a 2C-x compound, it's chemical name shows that more clearly when written as a 2C-x type compound: 4-(2-aminoethyl)-2,5-dimethoxyphenethylamine. Any activity will be dependant upon the lipophillic properties of the 2-aminoethyl group (it may turn out to be too hydrophillic to be very active), but who knows - it should have some sort of activity.

4 is a phenethylamine version of a dragonfly, but with nitrogen atoms where the oxygen atoms should be. As the 5-methoxy/furanyl oxygen of phenethylamine hallucinogens effectively fills the role of the indolic nitrogen, the two should be interchangable to a certain degree. Both have at least one lone pair of electrons for forming hydrogen bonds to the receptor protein, so structure 4 should work in theory.

5 & 6 are on the same principal as 4, only they are hemi-dragonflies with the indolic nitrogen replacing the oxygen in the one furanyl ring of said hemi-dragonfly. Because of this, the only useful groups attached to the sidechain nitrogen are likely to be hydrogens - alkyl groups will be like N-alkylating the nitrogen of phenethylamines.

7 is a complete unknown. It has the 2,4,6 type of substitution pattern, but as no studies have been carried out w.r.t. extending a methoxy group to a furanyl/dihydrofuranyl ring, they're anybody's guess (must say though, something tells me no, or not very likely as the lone pairs are just not in optimal position for formation of hydrogen bonds.

The out of position lone pair electrons idea also applies to compound 1. Compound 3 also seems unlikely as the 'stereochemistry' (I know there's no stereochemistry as such - I was just referring to bond length and angles) is wrong as well as the influence of the electronegativity of the oxygen atom on the lone pair orientation of the nitrogen atom (which is needed to form hydrogen bonds to receptor protein).

Although that's just my view from understanding the spatial orientation and positioning of charges/lone pairs of the compounds, the big test is to synthesise them and do receptor affinty trials.

PS I find .doc files crap to deal with, so I've redone the image as a jpeg
 

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2-[4-(Cyanomethyl)-2,5-dimethoxyphenyl]acetonitrile is commercially available so in theory all that would have to be done is a successful hydrogenation of this chemical. I dont know what yields would be like since I read that the acetonitrile route to mescaline is not as straight-forward in practice as it appears on paper. I would guess that it cannot be that prohibitively difficult to do although it is anyones guess whether or not it would be worth pursuing. Some modifications might need to be made like carrying the reaction out in liquid ammonia but you'll have to research it for yourself if you genuinely want to follow-it-up.
 
Fastandbulbous:
The idea behind structure 7 was the dragonfly of Shulgin´s pseudo- orientated DO's, which are somewhat lower in activity. Nichols made those pseudo dragonflies and screend them. "Translocation of the 5-alkoxy substituent of 2,5-dialkoxyarylalkylamines to the 6-position: effects on 5-HT2A/2C receptor affinity. Chambers, James J.; Kurrasch-Orbaugh, Deborah M.; Nichols, David E. School of Pharmacy and Pharmacal Sciences, Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA. Bioorganic & Medicinal Chemistry Letters (2002), 12(15), 1997-1999. "



Smyth:
A friend of mine once synthesized the unsubstituted 1,4-bisaminoethylbenzene from the nitrile. Reduction was conduced with borane in THF with excellent yield, but the solubility of the hydrochloric salt compound is comparable to a stone.
 
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Fastandbulbous:
The idea behind structure 7 was the dragonfly of Shulgin´s pseudo- orientated DO's, which are somewhat lower in activity. Nichols made those pseudo dragonflies and screend them. I currently can´t find the citation.
Click to expand...

Do you mean hemi-dragonfly, as there's only one aromatic ring attached to the benzene nucleus. The full psi-DOx dragonflies would be of the structure given below (attached jpeg)

PS. If you could find that Nichols paper, I'd be very grateful - thanks
 

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Nitriles can be hydrogenated easily with Raney Nickel in the presence of alcoholic Ammonia.The latter prevents formation of dimeric compounds,not sure about pharmacology of these dimers,could be toxic.
 
#2 is inactive...or at least the amphetamine homologue is. With the inactivity of that, I doubt the 2-carbon chain homologue is active.
 
morninggloryseed said:
#2 is inactive...or at least the amphetamine homologue is. With the inactivity of that, I doubt the 2-carbon chain homologue is active.
Click to expand...

Wow, I nominate "Swastikamine" as the name for the amphetamine homologue ;). (And no, I am not talking about the crooked Nazi swastika. Think Vishnu.)

On a more serious note, do you have a reference? I am not questioning what you're saying, I'm simply interested in knowing the full scoop.
 
This comes from private communication to me by a respected chemist who made it and tried it. I do not have any citation, you will just have to take my word. That's the best I can do.
 
MGS, Thanks for the information that the amphetamine homologue is inactive. But probably the residue at pos. 4 with the alpha methyl-group is simply too bulky. Up to what dose was this amph.-homologue tested?
What I still do not understand is, why tryptamines require two alkyl groups on the nitrogen, and PEAs must not have two alkyls. To my knowlege there is no active PEA with two N-alkyl residues. And in the tryptamine world there is AMT and it´s 5-MeO derivative the only unsubstituted and active dertvatives. Monoalkylated tryptamines seems also to be absolutely inactive (some are MAOIs). Can anybody explain this?
 
MGS, Thanks for the information that the amphetamine homologue is inactive. But probably the residue at pos. 4 with the alpha methyl-group is simply too bulky. Up to what dose was this amph.-homologue tested?
Click to expand...

Not really, DOPr (4-propyl-2,5-dimethoxyamphetamine) is active at quite low doses and the only difference between DOPr & the amphetamine version MGS mentions is an amino group; it's more likely that the amino group makes the 4 substituent too polar to fit into the receptor site successfully. If the 4-(2-aminoethyl)-2,5-dimethoxyamphetamine proved inactive, then it's almost certainly due to the group being too polar as the 2-aminoethyl group is smaller than an propyl group.


What I still do not understand is, why tryptamines require two alkyl groups on the nitrogen, and PEAs must not have two alkyls. To my knowlege there is no active PEA with two N-alkyl residues. And in the tryptamine world there is AMT and it´s 5-MeO derivative the only unsubstituted and active dertvatives. Monoalkylated tryptamines seems also to be absolutely inactive (some are MAOIs). Can anybody explain this?
Click to expand...

I somehow think that the compounds susceptability to degredation by MAO plays a small part in that (AMT & 5-MeOAMT are weak competetive inhibitors of MAO) and anything bigger than N,N-dimethyl on tryptamines makes it fairly resistant to MAO - something one alkyl group just doesn't seem to do until you get up to t-butyl (which is supposed to be active orally).

Only other thing I can think of is the way the conformation matches that of LSD - tryptamines overlay the LSD structure in a different way to the phenethylamines.

I've got no refs to back this - again just thinking aloud; other opinions would be welcome. We might come to some sort of discovery if everybody chips in with their ideas
 
EN21 said:
why tryptamines require two alkyl groups on the nitrogen, and PEAs must not have two alkyls. To my knowlege there is no active PEA with two N-alkyl residues.
Click to expand...

Macromerine (N,N-dimethyl-3,4-dimethoxy-beta-hydroxy-beta-phenethylamine) is said to be active, and has 1/5 the potency of mescaline in mumerous publications. However, I have yet to see a valid source for this, so I do not know how valid that claim is.
 
F&B,
Yea, sounds reasonable. But here is an other idea: You say that AMT is a weak competitive MAOI. Is it therefore metabolised by the MAO but only much slower, occupying it for that time or not?
I could also imagine that AMT inhibits by MAOI its own degradation allowing it to cross intact the BBB. If this would be right, AMT in combination with an really strong MAOI should be active in much lower doses?!?! This could explain its very slow onset. –Plain speculations!

Smyth!
Thanks for your comment. I am pretty sure that reduction of the amide to the indoline and subsequent oxidation to the indole leads to an active compound. But an other problem that might occur with all those chain relocated tryptamines is probably instability, since the indolic position 3 is the most active towards electrophilic attack and it is free accessible. I'm not sure, but it is not impossible.

Thanks for the note, MGS. This probably could also be named as N,O,O-trimethyl-epinephrine. When I calculate right, the dose range would then be about 1.75 grams, (maybe a tablespoonful). But since the 3,4-dimethoxy pattern is usually not the best for psychedelics, the N,N-dimethyl- 2,5-dimethoxy 4-anything beta hydroxy counterpart could be active in a much smaller range. Probably the beta hydroxy group accepts the N,N-double methylation of the PEA’s. –I try to add a picture.


EN21
 
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Don't like the look of 2,5-dimethoxy substitution with a beta hydroxy - it's too much like clinical pressor agents like methoxamine; that combined with Shulgin's experience with BOHD (massive blood pressure drop) is enough to convince me to stay well clear. It's due to the pressor effects that I'm even wary of 2,5-dimethoxy-4-X-cathinone derivative; one of their main metabolic routes is reduction of the beta-keto group to a beta hydroxy.
 
MGS: No problem, thanks for sharing :).

Hmm. I was under the impression that a beta-hydroxy group on a phenethylamine is not very conductive (but not completely abolishing) to CNS activity due to BBB issues (think Ephedrine). Would that explain why macromerine is less potent? This could also extend to the 2,5-dimethoxy version suggested?

Or am I missing something (such as another group in the structure that makes the molecule more BBB cross-able?)
 
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