Behavioral and neurochemical effects of 5-(4-[4-(5-Cyano-3-indolyl)-butyl)-butyl]-1-piperazinyl)-benzofuran-2-carboxamide (EMD 68843): a combined selective inhibitor of serotonin reuptake and 5-hydroxytryptamine(1A) receptor partial agonist

J Pharmacol Exp Ther. 2002 Sep;302(3):1220-7. doi: 10.1124/jpet.102.034280.

Abstract

5-(4-[4-(5-Cyano-3-indolyl)-butyl)-butyl]-1-piperazinyl)-benzofuran-2-carboxamide (EMD 68843; vilazodone) is a novel compound with combined high affinity and selectivity for the 5-hydroxytryptamine (5-HT) transporter and 5-HT(1A) receptors. EMD 68843 was tested as a prototype compound, which benefits from dual pharmacological effects that could increase extracellular 5-HT to levels higher than those produced by conventional selective serotonin reuptake inhibitors (SSRIs). In Sf9 cells, EMD 68843 increased guanosine 5'-O-(3-[(35)S]thiotriphosphate) binding to 69% of the magnitude of the full 5-HT(1A) receptor agonist R-(1)-trans-8-hydroxy-2-[N-n-propyl-N-(39-iodo-29-propenyl)] aminotetralin (8-OH-PIPAT), indicating that it is a partial agonist at 5-HT(1A) receptors. Acute, systemic administration of EMD 68843 produced a larger maximal increase of extracellular 5-HT than the SSRI fluoxetine in both the ventral hippocampus (HPv) (558 versus 274%) and the frontal cortex (FC) (527 versus 165%). Regional differences in the response to the two drugs were also observed. These effects may be attributed to the differential regulation of 5-HT release in the HPv and FC by 5-HT(1A) autoreceptors. When challenged with the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), EMD 68843-induced increases in extracellular 5-HT were greatly reduced in the HPv but to a lesser extent in the FC. In behavioral studies, EMD 68843 produced antidepressant-like effects in the forced swimming test in both rats and mice but only within a narrow dosage range. Like fluoxetine, EMD 68843 did not produce the symptoms of the 5-HT behavioral syndrome in rats but, unlike fluoxetine, pretreatment with EMD 68843 blocked expression of the 5-HT behavioral syndrome induced by 8-OH-DPAT. Taken together, the results show that EMD 68843 augments extracellular 5-HT levels in forebrain regions to a greater extent than fluoxetine. At higher doses, however, weak efficacy of EMD 68843 at postsynaptic 5-HT(1A) receptors may inhibit the expression of rodent antidepressant-like behaviors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 8-Hydroxy-2-(di-n-propylamino)tetralin / pharmacology
  • Animals
  • Antidepressive Agents, Second-Generation / pharmacology
  • Behavior, Animal / drug effects*
  • Benzofurans / pharmacology*
  • Brain Chemistry / drug effects*
  • Cell Line
  • Extracellular Space / drug effects
  • Extracellular Space / metabolism
  • Female
  • Fluoxetine / pharmacology
  • GTP-Binding Proteins / metabolism
  • Guanosine 5'-O-(3-Thiotriphosphate) / pharmacology
  • Indoles / pharmacology*
  • Microdialysis
  • Piperazines
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism
  • Protein Binding / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Serotonin / drug effects*
  • Receptors, Serotonin, 5-HT1
  • Serotonin Receptor Agonists / pharmacology*
  • Serotonin Uptake Inhibitors / pharmacology*
  • Swimming / psychology
  • Vilazodone Hydrochloride

Substances

  • Antidepressive Agents, Second-Generation
  • Benzofurans
  • Indoles
  • Piperazines
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT1
  • Serotonin Receptor Agonists
  • Serotonin Uptake Inhibitors
  • Fluoxetine
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • 8-Hydroxy-2-(di-n-propylamino)tetralin
  • GTP-Binding Proteins
  • Vilazodone Hydrochloride