Synthesis and serotonin receptor affinities of a series of trans-2-(indol-3-yl)cyclopropylamine derivatives

A series of four racemic ring-substituted trans-2-(indol-3-yl)cyclopropylam ine derivatives was synthesized and tested for affinity at the 5-HT1A recep tor, by competition with [H-3]-8-OH-DPAT in rat hippocampal homogenates, an d for affinity at the agonist-labeled cloned human 5-HT2A, 5-HT2B, and 5-HT 2C receptor subtypes. None of the compounds had high affinity for the 5-HT1 A receptor, with the 5-methoxy substitution being most potent (40 nM). At t he 5-HT2A and 5-HT2B receptor isoforms, most of the compounds lacked high a ffinity. At the 5-HT2C receptor, however, affinities were considerably high er. The 5-fluoro-substituted compound was most potent, with a K-i at the 5- HT2C receptor of 1.9 nM. In addition, the 1R,2S-(-) and 1S,2R-(+) enantiome rs of the unsubstituted compound were also evaluated at the 5-HT2 isoforms. While the 1R,2S enantiomer had higher affinity at the 5-HT2A and 5-HT2B si tes, the 1S,2R isomer had highest affinity at the 5-HT2C receptor. This rev ersal of stereoselectivity may offer leads to the development of a selectiv e 5-HT2C receptor agonist. The cyclopropylamine moiety therefore appears to be a good strategy for rigidification of the ethylamine side chain only fo r tryptamines that bind to the 5-HT2C receptor isoform.