4-Aryl-Substituted 2,5-Dimethoxyphenethylamines: Synthesis and Serotonin 5-HT2A Receptor Affinities

• Published in: Chemistry & biodiversity 2009-05, Vol.6 (5), p.692-704
• Main Authors: Trachsel, Daniel, Nichols, David E., Kidd, Stephanie, Hadorn, Marcel, Baumberger, Franz
• Format: Article
• Language: English
• Subjects: 4-aryl-2; 5-dimethoxy; Phenethylamines; Phenethylamines, 4‐aryl‐2,5‐dimethoxy; Receptors; Serotonin receptors; Structure-activity relationship (SAR)
• ISSN: 1612-1872; 1612-1880
• DOI: 10.1002/cbdv.200800235

A series of novel ligands for the serotonin 5‐HT2A/C receptor subtype bearing the 2‐phenylethylamine pharmacophore was synthesized and assayed for its 5‐HT2A 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‐HT2A 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 (Ki=32, 33, and 41nM, resp.), attests a rather remarkable tolerance for bulk in this location.