Synthesis and preliminary screening of novel indole-3-methanamines as 5-HT4 receptor ligands

Twenty-three indole-3-methanamines were designed, synthesized and evaluated as ligands for the 5-HT4 receptor. Compounds I-d, I-j, I-o, I-q and I-u showed good affinity at 100 μM and I-o was found to be only 5-fold less potent than the agonists serotonin (1) and 5-methoxytryptamine (2). Substitution on the 3-methanamine nitrogen clearly influenced activity with docking experiments into a homology model of the 5-HT4 receptor showing a range of interactions with these side chain substituents. This modelling work together with the SAR determined in this study has provided promising ideas for future synthetic work.

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