Desvenlafaxine succinate: A new serotonin and norepinephrine reuptake inhibitor

J Pharmacol Exp Ther. 2006 Aug;318(2):657-65. doi: 10.1124/jpet.106.103382. Epub 2006 May 4.


The purpose of this study was to characterize a new chemical entity, desvenlafaxine succinate (DVS). DVS is a novel salt form of the isolated major active metabolite of venlafaxine. Competitive radioligand binding assays were performed using cells expressing either the human serotonin (5-HT) transporter (hSERT) or norepinephrine (NE) transporter (hNET) with K(i) values for DVS of 40.2 +/- 1.6 and 558.4 +/- 121.6 nM, respectively. DVS showed weak binding affinity (62% inhibition at 100 microM) at the human dopamine (DA) transporter. Inhibition of [3H]5-HT or [3H]NE uptake by DVS for the hSERT or hNET produced IC50 values of 47.3 +/- 19.4 and 531.3 +/- 113.0 nM, respectively. DVS (10 microM), examined at a large number of nontransporter targets, showed no significant activity. DVS (30 mg/kg orally) rapidly penetrated the male rat brain and hypothalamus. DVS (30 mg/kg orally) significantly increased extracellular NE levels compared with baseline in the male rat hypothalamus but had no effect on DA levels using microdialysis. To mimic chronic selective serotonin reuptake inhibitor treatment and to block the inhibitory 5-HT(1A) autoreceptors, a 5-HT(1A) antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclo hexanecarboxamide maleate salt (WAY-100635) (0.3 mg/kg s.c.), was administered with DVS (30 mg/kg orally). 5-HT increased 78% compared with baseline with no additional increase in NE or DA levels. In conclusion, DVS is a new 5-HT and NE reuptake inhibitor in vitro and in vivo that demonstrates good brain-to-plasma ratios, suggesting utility in a variety of central nervous system-related disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Uptake Inhibitors / metabolism
  • Adrenergic Uptake Inhibitors / pharmacokinetics
  • Adrenergic Uptake Inhibitors / pharmacology*
  • Animals
  • Brain / metabolism
  • Brain Chemistry / drug effects
  • Cell Line
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cyclohexanols / metabolism
  • Cyclohexanols / pharmacokinetics
  • Cyclohexanols / pharmacology*
  • Desvenlafaxine Succinate
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Humans
  • Hypothalamus / metabolism
  • Male
  • Microdialysis
  • Norepinephrine Plasma Membrane Transport Proteins / metabolism
  • Protein Binding
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Selective Serotonin Reuptake Inhibitors / metabolism
  • Selective Serotonin Reuptake Inhibitors / pharmacokinetics
  • Selective Serotonin Reuptake Inhibitors / pharmacology*
  • Serotonin Plasma Membrane Transport Proteins / metabolism


  • Adrenergic Uptake Inhibitors
  • Cyclohexanols
  • Dopamine Plasma Membrane Transport Proteins
  • Norepinephrine Plasma Membrane Transport Proteins
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors
  • Desvenlafaxine Succinate