5-HT₂c receptor selectivity and structure-activity relationship of N-methyl-N-(1-methylpiperidin-4-yl)benzenesulfonamide analogs

Bioorg Med Chem Lett. 2012 Jan 1;22(1):347-52. doi: 10.1016/j.bmcl.2011.11.001. Epub 2011 Nov 15.

Abstract

Agonists of the 5-HT(2C) receptor have attracted much attention as therapeutic agents for the treatment of obesity. Subtype selectivity against other 5-HT(2) receptors is one of the most important prerequisites for reducing side effects. We present the synthesis of N-methyl-N-(1-methylpiperidin-4-yl)benzenesulfonamide analogs and their structure-activity relationship studies on 5-HT(2A) and 5-HT(2C) receptors. Although the compounds showed nanomolar activity to the 5-HT(2C) receptor, their selectivity against the 5-HT(2A) receptor was modest to low. Molecular modeling studies using homology modeling and docking simulation revealed that selectivity originated from subtype specific residues. The observed binding modes and receptor-ligand interactions provided us a clue for optimizing the selectivity against the 5-HT(2A) receptor.

MeSH terms

  • Amino Acid Sequence
  • Benzenesulfonamides
  • Computer Simulation
  • Drug Design
  • Humans
  • Inhibitory Concentration 50
  • Ligands
  • Models, Chemical
  • Models, Molecular
  • Molecular Conformation
  • Molecular Sequence Data
  • Piperidines / chemical synthesis*
  • Piperidines / pharmacology
  • Protein Binding
  • Receptor, Serotonin, 5-HT2C / chemistry*
  • Receptor, Serotonin, 5-HT2C / metabolism
  • Sequence Homology, Amino Acid
  • Serotonin / metabolism
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / pharmacology

Substances

  • Ligands
  • N-methyl-N-(1-methylpiperidin-4-yl)benzenesulfonamide
  • Piperidines
  • Receptor, Serotonin, 5-HT2C
  • Sulfonamides
  • Serotonin