Structure-Activity Relationship (SAR) of the Phenethylamines: A ...

Hallucinogenic Phenethylamines:
Ring Poly-Substitutions
• 2,4- and 2,5-dimethoxyAMP are active in
humans (20 – 60 mg dose)
• 3,4-DimethoxyAMP is most like
catecholamines, but not psychoactive
• 2,4,6-trimethoxyAMP is almost as potent as
2,4,5-trimethoxyAMP
• 2,3,4,5-TetramethoxyAMP was reported as
active in humans early on, but later study
suggests this is not the case
DOB
2C-B
Hallucinogenic Phenethylamines:
Side Chain Modifications
• Removal of α-CH 3 decreases potency in
hallucinogenic amphetamines
• Many stay within an order of magnitude
of α-methylated congener
• 2C-B and 2C-I are about 1/10 the potency
of amphetamine counterparts (DOB & DOI)
• Hallucinogen-like activity is higher for R-
enantiomer (in vitro and in vivo)
• Stereoselectivity of 3 – 6 fold (NOT
stereoespecificity)
• The α,α-Dimethyl compounds are inactive
Hallucinogenic Phenethylamines:
Mechanism of Action
• This is tricky…
• Some in vitro receptor data but difficult
model to reproducibly characterize in vivo
• Probably more direct postsynaptic agonist
activity than the other amphetamines
• Most important receptor seems to be the
5-HT 2 subtype
• 5-HT 1C is probably #2
• 5-HT 1A Hmmmmm……
• Tryptamines and LSD do hit 5-HT 1A
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