Synthesis and evaluation of new coumarin derivatives as potential atypical antipsychotics

Eur J Med Chem. 2014 Mar 3:74:427-39. doi: 10.1016/j.ejmech.2014.01.012. Epub 2014 Jan 15.

Abstract

In this paper, we report the synthesis of novel, potential antipsychotic coumarin derivatives combining potent dopamine D₂, D₃ and serotonin 5-HT(1A), 5-HT(2A) receptors properties. We describe the structure activity relationship that leads us to the promising derivative: 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy)-6-methyl-2,3-dihydrocyclopenta[c]chromen-4(1H)-one 27. The unique pharmacological features of compound 27 are a high affinity for dopamine D₂, D₃ and serotonin 5-HT(1A), 5-HT(2A) receptors, together with a low affinity for H₁ receptor (to reduce the risk of obesity under chronic treatment). In animal models, compound 27 inhibited apomorphine-induced climbing and MK-801-induced hyperactivity without observable catalepsy at the highest dose tested. In particular, compound 27 was more potent than clozapine.

Keywords: Atypical antipsychotics; Coumarin; Dopamine; Serotonin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipsychotic Agents / chemical synthesis
  • Antipsychotic Agents / pharmacology*
  • Behavior, Animal / drug effects
  • Coumarins / chemical synthesis
  • Coumarins / pharmacology*
  • Magnetic Resonance Spectroscopy
  • Mice
  • Spectrometry, Mass, Electrospray Ionization

Substances

  • Antipsychotic Agents
  • Coumarins