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-Hydroxytryptamine1A Receptor Partial Agonist

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 302; no. 3; p. 1220
• Main Authors: Michelle E. Page, John F. Cryan, Arthur Sullivan, Ashutosh Dalvi, Berangere Saucy, David R. Manning, Irwin Lucki
• Format: Journal Article
• Language: English
• Published: American Society for Pharmacology and Experimental Therapeutics 01.09.2002
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.102.034280

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.