Reformulating a Pharmacophore for 5-HT2A Serotonin Receptor Antagonists

ACS Chem Neurosci. 2016 Sep 21;7(9):1292-9. doi: 10.1021/acschemneuro.6b00162. Epub 2016 Jul 19.

Abstract

Several pharmacophore models have been proposed for 5-HT2A serotonin receptor antagonists. These typically consist of two aromatic/hydrophobic moieties separated by a given distance from each other, and from a basic amine. Although specified distances might vary, the models are relatively similar in their general construction. Because our preliminary data indicated that two aromatic (hydrophobic) moieties might not be required for such action, we deconstructed the serotonin-dopamine antipsychotic agent risperidone (1) into four smaller structural fragments that were thoroughly examined in 5-HT2A receptor binding and functional (i.e., two-electrode voltage clamp (TEVC) and intracellular calcium release) assays. It was apparent that truncated risperidone analogues behaved as antagonists. In particular, 6-fluoro-3-(1-methylpiperidin-4-yl)benzisoxazole (4) displayed high affinity for 5-HT2A receptors (Ki of ca. 12 nM) relative to risperidone (Ki of ca. 5 nM) and behaved as a potent 5-HT2A serotonin receptor antagonist. These results suggest that multiple aromatic (hydrophobic) moieties are not essential for high-affinity 5-HT2A receptor binding and antagonist activity and that current pharmacophore models for such agents are very much in need of revision.

Keywords: 3-(4-piperidinyl)benzisoxazoles; Risperidone; TEVC (two-electrode voltage clamp); antipsychotics; calcium release.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Barium / pharmacology
  • Calcium / metabolism
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / genetics
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / metabolism
  • HEK293 Cells
  • Humans
  • Hydrophobic and Hydrophilic Interactions / drug effects
  • Ketanserin / pharmacokinetics
  • Ketanserin / pharmacology
  • Membrane Potentials / drug effects*
  • Membrane Potentials / genetics
  • Mutation / genetics
  • Oocytes
  • Protein Binding / drug effects
  • Receptor, Serotonin, 5-HT2A / genetics
  • Receptor, Serotonin, 5-HT2A / metabolism
  • Risperidone / pharmacology
  • Serotonin / pharmacology
  • Serotonin 5-HT2 Receptor Antagonists / chemical synthesis*
  • Serotonin 5-HT2 Receptor Antagonists / chemistry
  • Serotonin 5-HT2 Receptor Antagonists / pharmacology*
  • Serotonin Antagonists / pharmacokinetics
  • Serotonin Antagonists / pharmacology
  • Tritium / pharmacokinetics
  • Xenopus laevis

Substances

  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • Receptor, Serotonin, 5-HT2A
  • Serotonin 5-HT2 Receptor Antagonists
  • Serotonin Antagonists
  • Tritium
  • Barium
  • Serotonin
  • Ketanserin
  • Risperidone
  • Calcium