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

Serotonin Releasers:
MDA – Optical Isomers
S-(+)-MDA
• Behavioral scoring in mice showed LSDlike
effect of racemic MDA are due totally
to the R-(-) isomer
• The S-(+) isomer possesses amphetamine
like activity
• In cats, the S-(+) isomer produces a
significant pressor response blocked by
• Pretreatment with reserpine (depleted
endogenous NE stores)
• Pretreatment with phenoxybenzamine
(α-adrenergic antagonist)
Serotonin Releasers:
MDA – Optical Isomers
S-(+)-MDA
• Indirect adrenergic and 5-HT releasing
actions are stereoselective for S-
• In synaptosomes:
• Potent releaser of 5-HT
• Moderately potent 5-HT uptake inhibitor
• Very potent inhibitor of NE uptake
• Modest effect on inhibition of DA uptake
• 2 – 3 fold S- over R- stereoselectivity
• S-(+)-MDA has some amphetamine-like
activity but the primary discriminative cue
appears to be serotonergic
Serotonin Releasers:
N-Substitution
R-(-)-MDMA
• MDMA first synthesized in 1912
• In vitro, pharmacology is similar to MDA
• R-MDMA has higher affinity at 5-HT 2
• In vivo, S-MDMA is more potent
• Discriminative cue (MDMA) is not blocked
by ketanserin (5-HT 2 antagonist)
• In drug discrimination studies, R-(-)-MDA
substitutes for hallucinogenic training
drugs, but R-(-)-MDMA does not
• N-Methylation of MDA abolishes R-
(hallucinogenic) activity, but has little effect
on the S- (5-HT and catecholamine) activity
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