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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.JP

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.

Authors+Show Affiliations

Department of Psychiatry, University of Pennsylvania, 415 Curie Boulevard, Philadelphia, PA 19104-6140, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

12183683

Citation

Page, Michelle E., et al. "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." The Journal of Pharmacology and Experimental Therapeutics, vol. 302, no. 3, 2002, pp. 1220-7.
Page ME, Cryan JF, Sullivan A, et al. 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;302(3):1220-7.
Page, M. E., Cryan, J. F., Sullivan, A., Dalvi, A., Saucy, B., Manning, D. R., & Lucki, I. (2002). 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. The Journal of Pharmacology and Experimental Therapeutics, 302(3), 1220-7.
Page ME, et al. 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;302(3):1220-7. PubMed PMID: 12183683.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Page,Michelle E, AU - Cryan,John F, AU - Sullivan,Arthur, AU - Dalvi,Ashutosh, AU - Saucy,Berangere, AU - Manning,David R, AU - Lucki,Irwin, PY - 2002/8/17/pubmed PY - 2002/9/19/medline PY - 2002/8/17/entrez SP - 1220 EP - 7 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 302 IS - 3 N2 - 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/12183683/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_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=12183683 DB - PRIME DP - Unbound Medicine ER -