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

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Hallucinogenic Phenethylamines Mescaline 3,4,5-Trimethoxyamphetamine • Mescaline was the starting point of the substituted phenethylamine genre • Mescaline begat TMA in 1955 • Nearly 200 derivatives have been evaluated for hallucinogenic activity • Shulgin’s PIHKAL is perhaps the most comprehensive collation of data to date Hallucinogenic Phenethylamines: N-Substitution • N-alkylation of hallucinogenic amphetamines dramatically attenuates or even abolishes hallucinogenic activity • Both receptor (5-HT 2 , 5HT 1C ) affinity and in vivo activity are diminished • N-CH 3 reduces hallucinogenic activity by about an order of magnitude • N,N-Dialkylation (even with methyl groups), completely abolishes hallucinogenic activity • An N-alkyl group larger than CH 3 or incorporation of the nitrogen into a heterocyclic ring leads to inactivity Hallucinogenic Phenethylamines: Aromatic Ring Substitution • 3,4,5-Trimethoxy pattern (e.g. mescaline) actually gives lowest potency hallucinogens • Moving 3-OCH 3 to the 2 position and/or replacing the 4-OCH 3 with a more hydrophobic group gives highly active hallucinogenic compounds • 2,4,5-trisubstituted with 2 and 5 substituents as OCH 3 are most active 12
Hallucinogenics based on 2,5-Dimethoxyamphetamine R Trivial Name Est Dose (mg)* H 2,5-DMA 80 – 160 OCH 3 TMA-2 20 – 40 OCH 2 CH 3 MEM 20 – 50 SCH 3 p-DOT 5 – 10 NO 2 DON 3 – 4.5 CH 3 DOM 3 – 10 CH 2 CH 3 DOEt 2 – 6 CH 2 CH 2 CH 3 DOPr 2.5 – 5 Br DOB 1 – 3 I DOI 1.5 – 3 CF 3 DOTFM Animals Only *Data compiled from Shulgin & Shulgin (1991) Hallucinogenics based on 2,5-Dimethoxyamphetamine 2,5-Dimethoxyamphetamine • Are differences a result of electronics • Probably not – both alkyl and highly electronegative groups (e.g. NO 2 , CF 3 ) are highly active • Greatest activity seems to be in congeners with relatively hydrophobic parasubstituent which is fairly resistant to oxidative metabolism Hallucinogenic Phenethylamines: 4-Substituent Orientation A B • 4-substituent may force 5-OCH 3 into “anti” orientation • Compound A lacks “LSD-like” activity while B is as potent as the flexible analog, DOB • H-bond donor in the receptor site that needs this orientation of the O lone pair • This orientation of the OCH 3 group is required to make the aromatic system appear electronically similar to the indole nucleus of 5-HT 13
Page 1 and 2: Structure-Activity Relationship (SA
Page 3 and 4: Initial SAR 2-Phenethylamine • No
Page 5 and 6: Catecholamine Releasers: Benzylic C
Page 7 and 8: Catecholamine Releasers: Mechanism
Page 9 and 10: Serotonin Releasers: MDA - Optical
Page 11: Serotonin Releasers: Mechanism of A
Page 15 and 16: Hallucinogenic Phenethylamines: Rin

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

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