Discovery of a new class of potential multifunctional atypical antipsychotic agents targeting dopamine D3 and serotonin 5-HT1A and 5-HT2A receptors: design, synthesis, and effects on behavior

J Med Chem. 2009 Jan 8;52(1):151-69. doi: 10.1021/jm800689g.

Abstract

Dopamine D(3) antagonism combined with serotonin 5-HT(1A) and 5-HT(2A) receptor occupancy may represent a novel paradigm for developing innovative antipsychotics. The unique pharmacological features of 5i are a high affinity for dopamine D(3), serotonin 5-HT(1A) and 5-HT(2A) receptors, together with a low affinity for dopamine D(2) receptors (to minimize extrapyramidal side effects), serotonin 5-HT(2C) receptors (to reduce the risk of obesity under chronic treatment), and for hERG channels (to reduce incidence of torsade des pointes). Pharmacological and biochemical data, including specific c-fos expression in mesocorticolimbic areas, confirmed an atypical antipsychotic profile of 5i in vivo, characterized by the absence of catalepsy at antipsychotic dose.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipsychotic Agents / chemical synthesis*
  • Antipsychotic Agents / chemistry
  • Antipsychotic Agents / classification
  • Antipsychotic Agents / pharmacology*
  • Behavior, Animal / drug effects*
  • Binding Sites
  • Drug Design*
  • Drug Evaluation, Preclinical
  • Humans
  • Ligands
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Protein Binding
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Receptor, Serotonin, 5-HT2A / metabolism*
  • Receptors, Dopamine D3 / metabolism*
  • Structure-Activity Relationship

Substances

  • Antipsychotic Agents
  • Ligands
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Dopamine D3
  • Receptor, Serotonin, 5-HT1A