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

Serotonin Releasers:
Mechanism of Action
• Not just 5-HT uptake inhibitors
• They also actively cause release of
endogenous 5-HT
• Likely involves 5-HT transporter protein
• Indirect action with amine transporters
(e.g. MDMA-5-HT exchange) is probably
also involved
• Passive diffusion into vesicles and
transport out of the neuron by reverse
action of the uptake pump
Serotonin Releasers:
SAR Summary
• Monosubstitution at the 4-position gives
significant 5-HT activity
• Halogens and OCH 3 have appreciable
catecholamine releasing actions
• A 3-CF 3 group (e.g. fenfluramine) gives
relatively 5-HT selective agent
• A 3,4-dioxole disubstitution gives agents
with 5-HT and catecholamine activity (MDA)
• Primary amine is most potent
• Extension of α-CH 3 to α-Et improves 5-HT
action by attenuating catecholamine effects
• Longer chains are not allowable
Hallucinogens
• Called by various names –
psychotomimetics, hallucinogens,
psychedelics
• Jaffe argued that ‘psychedelic’ was the
most appropriate moniker
• “The feature that distinguishes the
psychedelic agents from other classes of
drugs is their capacity to induce states of
altered perception, thought and feeling that
are not experienced otherwise except in
dreams or at times of religious exaltation.”
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