New 1-arylindoles based serotonin 5-HT7 antagonists. Synthesis and binding evaluation studies

• Indole analogues of MR25003 were synthesized.
• 5-HT7 and 5-HT1A binding affinities of indole derivatives were evaluated.
• Two compounds displayed low nanomolar binding affinity for 5-HT7 receptors.
• Acceptable selectivity profile versus other 5-HT receptors was observed for the 1-(naphthyl)indole derivative.
• The 1-(naphthyl)indole derivative was pharmacology characterized as a 5-HT7 antagonist.

Based on 5-HT1A and 5-HT7 ligand MR25003 scaffold, a new series of 1-aryl indole analogues were prepared and evaluated against 5-HT7 receptors. Modulations of aryl moieties provided a large number of new indolic derivatives. Most of compounds tested have displayed 5-HT7 affinity in the nanomolar range. Among them, 1-(naphthyl)indole derivative 3p (Ki (5-HT7) = 4.5 nM) showed also a good selectivity over 5-HT1A, 5-HT2A and 5-HT6 receptors. This compound was pharmacology characterized as an antagonist.

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