Design and synthesis of new homo and hetero bis-piperazinyl-1-propanone derivatives as 5-HT7R selective ligands over 5-HT1AR

Bioorg Med Chem Lett. 2016 Aug 15;26(16):4052-6. doi: 10.1016/j.bmcl.2016.06.080. Epub 2016 Jun 28.

Abstract

In this work we report the discovery of new homo and hetero bis-piperazinyl-1-propanone derivatives as selective ligands for 5-HT7 over 5-HT1A receptor. These newly synthesized compounds possess a 4-arylpiperazine linked through an acyl spacer to another substituted piperazine system and were tested for their binding properties on human cloned 5-HT1A and 5-HT7 serotonin receptors. Among these, phenyl, 4- and 2-chlorophenyl, 2-methoxyphenyl, 2-pyridyl, and 2-pyrimidyl derivatives 15, 24, 25, and 27-29 displayed nanomolar affinity values for the 5-HT7 receptor (Ki 23.5-52.0nM) and no affinity for the 5-HT1A receptor.

Keywords: 5-HT(7) selective ligands; Bivalent ligand approach; Hetero bis-piperazine; Homo bis-piperazine; Serotonin receptors.

MeSH terms

  • Drug Design*
  • Humans
  • Kinetics
  • Ligands
  • Piperazine
  • Piperazines / chemistry*
  • Propane / analogs & derivatives*
  • Propane / chemical synthesis
  • Propane / metabolism
  • Protein Binding
  • Receptors, Serotonin / chemistry
  • Receptors, Serotonin / metabolism*
  • Serotonin Antagonists / chemical synthesis*
  • Serotonin Antagonists / chemistry
  • Serotonin Antagonists / metabolism
  • Structure-Activity Relationship

Substances

  • Ligands
  • Piperazines
  • Receptors, Serotonin
  • Serotonin Antagonists
  • serotonin 5 receptor
  • serotonin 7 receptor
  • Piperazine
  • Propane