Phenethylamine analogues of tryptamines (& vice versa)?

[TheAppleCore]

Forgive my limited understanding of chemistry.

So, aMT, as I understand it, is essentially the tryptamine analogue of amphetamine, with aMT being alpha-methyltryptamine and amphetamine being alpha-methylphenethylamine. They have a number of interesting parallels, both in their subjective effects, and in their pharmacology.

I'm wondering if this tryptamine/phenethylamine analogue concept can be taken any further? Can we develop new and potentially interesting psychedelic compounds by taking a well known and positively received tryptamine like 4-HO-DMT, and synthesizing its phenethylamine analogue, 4-hydroxy-dimethylphenethylamine?

 

[sekio]

No, phenethylamines and tryptamines bind at different sites on the 5-HT2aR. (site of hallucinogenic activity) Moreover, phenethylamines bind to a wider variety of targets than tryptamines (like e.g. monoamine transporters)

4-hydroxy-phenethylamines are too polar to provide good blood-brain crossing, they are used as e.g. pupil dialators and decongestants. Hordenine (N,N-dimethyl-4-hydroxy-PEA) is a known compound and is present in mescal cactus, but it lacks any hallucinogenic effect.

N-alkylation of tryptamines seems mandatory for action (see: DMT more active than n-methyl-T which in turn is more active than straight tryptamine) whereas alkylation of phenethylamines usually decreases hallucinogenic potency (2c-x vs N-methyl-2c-x).

Shulgin, in PiHKAL/TiHKAL pointed out this quirk. It seems that the two structures would correspond quite nicely but in actuality they are two seperate chemical classes. Compounds like amphetamine and methamphetamine do not bind effectively to 5-HT2a. AMT does, however.

I strongly suggest flipping through PiHKAL and TiHKAL and reading Sasha's commentary.