Towards the development of 5-HT₇ ligands combining serotonin-like and arylpiperazine moieties

Eur J Med Chem. 2014 Jun 10:80:8-35. doi: 10.1016/j.ejmech.2014.04.034. Epub 2014 Apr 13.


Many known 5-HT7 ligands contain either a serotonin-like or an arylpiperazine structure that, in published SAR studies, are generally supposed to bind the same receptor pocket. Conversely, we explored the hypothesis that two such moieties can co-exist in the same ligand, binding to different pockets. We thus designed and synthesized a set of compounds including both a 5-hydroxyindol-3-ylethyl and a 1-arylpiperazine moieties connected by a short linker. The compounds were tested for their affinity for human 5-HT7 serotonin receptor. We further prepared a novel series of 5-HT7 ligands, where the 5-hydroxyindol-3-ylethyl moiety was bioisosterically replaced by a 3-hydroxyanilinoalkyl one. Among the newly synthesized compounds, potent ligands at the 5-HT7 receptor, behaving as antagonists in functional tests, were identified, even if they showed limited subtype selectivity. Docking studies within a model of the 5-HT7 receptor showed that the binding site can actually accommodate both moieties, with the serotonin-like one in the putative orthosteric site and the arylpiperazine one occupying an accessory pocket. The present results demonstrate that it is possible to devise and develop new 5-HT7 ligands merging two privileged structures in the same molecule.

Keywords: 5-HT(7); Chemical synthesis; Medicinal chemistry; Molecular modeling; Serotonin; Structure–activity relationships.

MeSH terms

  • Biomimetic Materials / chemical synthesis
  • Biomimetic Materials / chemistry*
  • Biomimetic Materials / metabolism*
  • Drug Design*
  • Humans
  • Ligands
  • Molecular Docking Simulation
  • Piperazines / chemistry*
  • Protein Conformation
  • Receptors, Serotonin / chemistry
  • Receptors, Serotonin / metabolism*
  • Serotonin / chemistry*
  • Structure-Activity Relationship


  • Ligands
  • Piperazines
  • Receptors, Serotonin
  • serotonin 7 receptor
  • Serotonin