Synthesis and biological investigation of coumarin piperazine (piperidine) derivatives as potential multireceptor atypical antipsychotics

J Med Chem. 2013 Jun 13;56(11):4671-90. doi: 10.1021/jm400408r. Epub 2013 May 31.


The discovery and synthesis of potential and novel antipsychotic coumarin derivatives, associated with potent dopamine D2, D3, and serotonin 5-HT1A and 5-HT2A receptor properties, are the focus of the present article. The most-promising derivative was 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl)butoxy)-4-methyl-8-chloro-2H-chromen-2-one (17m). This derivative possesses unique pharmacological features, including high affinity for dopamine D2 and D3 and serotonin 5-HT1A and 5-HT2A receptors. Moreover, it possesses low affinity for 5-HT2C and H1 receptors (to reduce the risk of obesity associated with chronic treatment) and hERG channels (to reduce the incidence of torsade des pointes). In animal models, compound 17m inhibited apomorphine-induced climbing behavior, MK-801-induced hyperactivity, and the conditioned avoidance response without observable catalepsy at the highest dose tested. Further, fewer preclinical adverse events were noted with 17m compared with risperidone in assays that measured prolactin secretion and weight gain. Acceptable pharmacokinetic properties were also noted with 17m. Taken together, 17m may constitute a novel class of drugs for the treatment of schizophrenia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipsychotic Agents / chemical synthesis*
  • Antipsychotic Agents / pharmacology
  • Antipsychotic Agents / toxicity
  • Avoidance Learning / drug effects
  • Biological Availability
  • Coumarins / chemical synthesis*
  • Coumarins / pharmacology
  • Coumarins / toxicity
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
  • Humans
  • In Vitro Techniques
  • Isoxazoles / chemical synthesis*
  • Isoxazoles / pharmacology
  • Isoxazoles / toxicity
  • Lethal Dose 50
  • Mice
  • Motor Activity / drug effects
  • Prolactin / blood
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT1A / metabolism
  • Receptor, Serotonin, 5-HT2A / metabolism
  • Receptors, Dopamine D2 / metabolism
  • Receptors, Dopamine D3 / metabolism
  • Structure-Activity Relationship
  • Weight Gain / drug effects


  • 7-(4-(4-(6-fluorobenzo(d)isoxazol-3-yl)-piperidin-1-yl)butoxy)-4-methyl-8-chloro-2H-chromen-2-one
  • Antipsychotic Agents
  • Coumarins
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • Isoxazoles
  • KCNH2 protein, human
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3
  • Receptor, Serotonin, 5-HT1A
  • Prolactin