Desvenlafaxine succinate: A new serotonin and norepinephrine reuptake inhibitor.
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Deecher DC, Beyer CE, Johnston G, Bray J, Shah S, Abou-Gharbia M, Andree TH
Desvenlafaxine succinate: A new serotonin and norepinephrine reuptake inhibitor.
J Pharmacol Exp Ther. 2006 Aug;318(2):657-65. Epub 2006 May 4.
- PubMed ID
- 16675639 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Desvenlafaxine Sodium-dependent noradrenaline transporter Protein Humans YesInhibitorDetails Desvenlafaxine Sodium-dependent serotonin transporter Protein Humans YesInhibitorDetails - Binding Properties
Drug Target Property Measurement pH Temperature (°C) Desipramine Sodium-dependent noradrenaline transporter Ki (nM) 2.1 N/A N/A Details Desipramine Sodium-dependent noradrenaline transporter Ki (nM) 4.1 N/A N/A Details Desipramine Sodium-dependent noradrenaline transporter Ki (nM) 3.9 N/A N/A Details Fluoxetine Sodium-dependent serotonin transporter Ki (nM) 7 N/A N/A Details Fluoxetine Sodium-dependent serotonin transporter Ki (nM) 10.3 N/A N/A Details Mazindol Sodium-dependent dopamine transporter Ki (nM) 18 N/A N/A Details