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

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Stereochemistry of the α-Carbon • S–(+)-amphetamine is more potent “amphetamine-like” enantiomer • More on what this means in a bit • There is a 4 – 10 fold stereoselective preference depending on assay used Catecholamine Releasers: Ring Substitution ortho- meta- para- • Rats trained to distinguish 1 mg/kg (+)-AMP from saline • ED 50 for (+)-AMP = 0.42 mg/kg • ED 50 for ortho-CH 3 -AMP = 4.1 mg/kg • meta- and para- require MUCH higher doses • Recall that ortho- is the 2-position, meta- is 3 and para- is 4. Catecholamine Releasers: N-Substitution R 1 R 2 Potency (%) H H 100 H CH 3 200 H CH 2 CH 3 50 H CH 2 CH 2 CH 3 50 CH 3 CH 3 20 • N-Et and N-OH give nearly complete substitution in (+)-AMP trained rats • Tertiary amines are dealkylated to more potent secondary amines in vivo • Monoamine transport systems can accommodate either primary or N-methyl substituted amines 4
Catecholamine Releasers: Benzylic Carbon Oxidation S-(+)-Amphetamine Cathinone • Generally good retention of activity • ED 50 values are about equal for cathinone and amphetamine • Rats trained on saline vs (+)-AMP showed (+/-)-cathinone to be equipotent to (+)-AMP • More potent congeners have S- absolute configuration at the α-carbon • In (+)-AMP trained rats, S- is about double racemic potency and R- is ~30% Catecholamine Releasers: Diethylpropion Diethylpropion Ethcathione • Diethylpropion has low monoamine transporter affinity • Prodrug for ethcathinone • Ethcathinone has weak 5-HT & DA activity • NE effects are 10 – 20 fold greater • Selective NE releasing agent Catecholamine Releasers: Benzylic Carbon Oxidation Cathinone Ephedrine Norepinephrine • Adding a second stereocenter creates diastereomers Pseudoephedrine Ephedrine • R-absolute configuration has greatest affinity at adrenergic receptors 5
Page 1 and 2: Structure-Activity Relationship (SA
Page 3: Initial SAR 2-Phenethylamine • No
Page 7 and 8: Catecholamine Releasers: Mechanism
Page 9 and 10: Serotonin Releasers: MDA - Optical
Page 11 and 12: Serotonin Releasers: Mechanism of A
Page 13 and 14: Hallucinogenics based on 2,5-Dimeth
Page 15 and 16: Hallucinogenic Phenethylamines: Rin

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

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