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Benzylic Ar-C(=CH2)-R 5HT2a agonists.

J

joystick

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A week or so ago, I noticed some chemical structures in the Gallery here on bluelight that were said to be 5-HT2a receptor subtype agonists. Most of the structures had already been covered by PiHKAL, but each seemed to have an Ar-C(=CH2)-R moiety, where Ar stands for "aryl" and "R" stands for "rest of molecule, aliphatic," at their respective benzylic positions.

A simple methyl Wittig reaction of methylone or methcathinone should produce this structural feature, I would imagine, but I want to see the chemistry section of the original studies to determine how exactly these compounds were in fact synthesized.

Anyway, can anybody point out a link to the journal article(s) where these structures orginated? I doubt if many of us have had the opportunity to try one of these compounds yet, but are they said to be of equipotency to the amphetamines and MD-amphetamines in terms of neurotransmitter agonism? (For example, an methcathinone and methylone, amphetamine analogues of the Ar-C(O)-R type where the R is -CH(CH3)NH2 and the Ar stands for "aromatic," are approximately one-third as potent drugs as their amphetamine counterparts, methamphetamine and MDMA respectively.)

I have a feeling this scientific author used this minor structural modification to make his paper just barely worthy of publication, but you never know. That C=C double bond may interact with its vicinal aromatic pi system in some kind of positive way, and a new class of PEAs (all of which include the 2C's, the amphetamines, the cathinones and the phenidates) opens the door for some kind of novel, pseudo-legal research chemicals of the phenyl-C(=CH2)CH(CH3)NH2 PEA subtype, especially of the MDMA and methamphetamine types.
 
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It's not a paper, there are no synthesis routes and these compounds haven't appeared anywhere before (to my knowledge). Most of the scribblings were just bits from various sources pulled together to document how the SAR studies for the 5HT2a receptor are going.

The phenylbutenes are just my two pennethworth about where it might be good to look next. The reason I came up with the phenylbutene structure was to do with taking bits of SAR info from here and there about BOx series compounds, how they double the potency of the plain phenethylamine structure. Also how it ties in with electrostatic charges, lone pair electrons, planar molecules and the activity of psilocin.

It would be very nice if someone would make some of them, in order to find out how they matched against other side chain modifications. I know the alpha methyl BOx series are more potent than their equivalent amphetamines (that Dave Nichols chap again). This is merely adopting a part of the structure from LSD, as it is so potent a compound. It acts as one of the points of electrostatic attraction within the protein receptor structure.

I know I could be wrong, but I'm buggered if I can see a fault in my reasoning (This is what I did for my M.Sc. - SAR studies, but not of hallucinogens - shame!), there's too much that's right about its configuration and the way the charge separation occurs (I know a hunch isn't good science, but it's one of the (few!) things that I know I really understand).

Hopefully, somebody with a good synthetic understanding will get curious and whip some up for testing
 
the Wittig reaction

I think someone could probably do a Wittig reaction on methylone to convert its Ar-C(O)-R, where Ar = 1,3-benzodioxole and
R = CH(CH3)NHCH3, to the Ar-C(=CH2)-R analogue.

The same could probably be done with methcathinone, which itself can be made from pseudoephedrine and chlorox and other stuff, for the meth analogue.
 
Thing is, the two examples you've mentioned (methylone and methcathinone), don't act via the 5HT2a receptor in the first place, so they're not good candidates to do this to in the first place. I was thinking more about derivatives of the 4-x-2,5-dimethoxyphenethylamines/amphetamines.
 
>I know the alpha methyl BOx series
>are more potent than their equivalent
>amphetamines (that Dave Nichols chap again).

Is this from private communications, or is there a journal article somewhere I've missed/forgotten about that discusses the "amphetamine" BOx analogues?

Also, fastandbulbous, what are your feelings about the possible activity of 3-phenyl-1-propen-2-amines and 2-phenyl-2-propen-1-amines with the 4-X-2,5-dimethoxy substitution pattern? The latter of the two seems most appealing. It seems to me that the most interesting of psychedelics (with a few notable exceptions) are the ones without the alpha-methyl substitution. Potency isn't everything, and a two-day experience is far from a plus in my book.
 
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^ 3-phenyl-2-aminopropene would be a compound with the NH2 group attached to a carbon that had a double bond also attached. This would spontaneously rearrange (a la keto-enol tautomerism) to the imine compound, which because of it's instability would hydrolyse to the phenylacetone and ammonia.

The 2-phenyl-3-aminopropenes (numbering should start from the double bond carbon to keep nomenclature bods happy!) are basically the alpha-desmethyl version of the original structures; they should be active (pending activity of the 2-phenyl-3-aminobutene derivatives) - probably more potent than the corresponding 2C-X compounds.

You never know; because of the beta-methylene group, it might be resistant to metabolism by MAO - that would mean that the 2,4,5-trimethoxy compound might be active and the corresponding 4-alkoxy homologues (equiv to the 2C-O-x compounds that are inactive as phenethylamines because of degredation by MAO)
 
>equiv to the 2C-O-x compounds that are
>inactive as phenethylamines
>because of degredation by MAO

We cant say the 2C-O series is inactive until 2C-O-2, 2C-O-21, and the 4-allyloxy analogue are tried! :)
 
From structural features, you can come to a pretty convincing conclusion especially when the active site of an enzyme has been characterized. That's the whole basis of SAR research - it's also metabolic enzymes as well as receptors
 
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