4‐Aryl‐Substituted 2,5‐Dimethoxyphenethylamines: Synthesis and Serotonin 5‐HT2AReceptor Affinities

A series of novel 2-phenylethylamine compounds with a 4'-aryl substituent was synthesized and tested for binding affinity at the serotonin 5-HT(2A) receptor. Most compounds acted as antagonists with generally low affinity, except for a few with substituents at the 4''-position. The 4''-butyl, 4''-phenyl, and 4'-naphthyl derivatives showed relatively high affinity, with K(i) values of 32, 33, and 41 nM, respectively, indicating tolerance for bulky groups at this location. The 4'-aryl moiety was introduced via a palladium-catalyzed Suzuki reaction.

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Abstract

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 41nM, resp.), attests a rather remarkable tolerance for bulk in this location.