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4‐Aryl‐Substituted 2,5‐Dimethoxyphenethylamines: Synthesis and Serotonin 5‐HT 2A Receptor Affinities
Author(s) -
Trachsel Daniel,
Nichols David E.,
Kidd Stephanie,
Hadorn Marcel,
Baumberger Franz
Publication year - 2009
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.200800235
Subject(s) - chemistry , moiety , pharmacophore , aryl , substituent , stereochemistry , ethylamine , affinities , biphenyl , 5 ht receptor , binding affinities , receptor , phenethylamines , serotonin , organic chemistry , alkyl , biochemistry
A series of novel ligands for the serotonin 5‐HT 2A/C receptor subtype bearing the 2‐phenylethylamine pharmacophore was synthesized and assayed for its 5‐HT 2A receptor binding affinity. As the 4′‐aryl‐substituted 2‐(2,5‐dimethoxyphenyl)ethylamines were previously unknown, an initial series of twelve compounds was chosen to obtain initial insight into their structure–activity relationships. The 4′‐aryl moiety was introduced in moderate‐to‐high yield by a Pd‐catalyzed Suzuki reaction of twelve arylboronic acids with N ‐Boc‐protected 2‐(2,5‐dimethoxy‐4‐iodophenyl)ethylamine ( 8 ). N ‐Boc Deprotection then afforded the novel 2‐phenylethylamines 5a – 5l . Additionally, biphenyl compound 6 lacking the 5′‐MeO substituent was prepared, starting from 2‐methoxy‐4‐hydroxybenzaldehyde. Except for 5l , all of the compounds proved to be antagonists with generally low affinity at the rat 5‐HT 2A receptor. Substituents are generally not well tolerated on the 4′‐aryl moiety, except in the 4″‐position. Indeed, the relatively high affinity of the 4″‐butyl‐, 4″‐phenyl‐, and 4′‐naphthyl‐substituted compounds 5i, 5k , and 5e , respectively ( K i =32, 33, and 41n M , resp.), attests a rather remarkable tolerance for bulk in this location.