Synthesis, binding affinity, and molecular docking analysis of new benzofuranone derivatives as potential antipsychotics

J Med Chem. 2008 Oct 9;51(19):6085-94. doi: 10.1021/jm800602w. Epub 2008 Sep 11.


The complex etiology of schizophrenia has prompted researchers to develop clozapine-related multitarget strategies to combat its symptoms. Here we describe a series of new 6-aminomethylbenzofuranones in an effort to find new chemical structures with balanced affinities for 5-HT2 and dopamine receptors. Through biological and computational studies of 5-HT2A and D2 receptors, we identified the receptor serine residues S3.36 and S5.46 as the molecular keys to explaining the differences in affinity and selectivity between these new compounds for this group of receptors. Specifically, the ability of these compounds to establish one or two H-bonds with these key residues appears to explain their difference in affinity. In addition, we describe compound 2 (QF1004B) as a tool to elucidate the role of 5-HT2C receptors in mediating antipsychotic effects and metabolic adverse events. The compound 16a (QF1018B) showed moderate to high affinities for D2 and 5-HT2A receptors, and a 5-HT2A/D2 ratio was predictive of an atypical antipsychotic profile.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antipsychotic Agents / chemical synthesis*
  • Antipsychotic Agents / chemistry*
  • Antipsychotic Agents / pharmacology
  • Benzofurans / chemical synthesis*
  • Benzofurans / chemistry*
  • Benzofurans / pharmacology
  • Binding, Competitive
  • Cloning, Molecular
  • Computer Simulation*
  • Crystallography, X-Ray
  • Humans
  • Hydrogen Bonding
  • Models, Chemical*
  • Models, Molecular
  • Molecular Structure
  • Receptor, Serotonin, 5-HT2A / chemistry
  • Receptor, Serotonin, 5-HT2A / drug effects
  • Receptor, Serotonin, 5-HT2C / chemistry
  • Receptor, Serotonin, 5-HT2C / drug effects
  • Receptors, Dopamine D2 / chemistry
  • Receptors, Dopamine D2 / drug effects
  • Sequence Alignment / methods
  • Structure-Activity Relationship


  • Antipsychotic Agents
  • Benzofurans
  • Receptor, Serotonin, 5-HT2A
  • Receptor, Serotonin, 5-HT2C
  • Receptors, Dopamine D2