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Received for publication March 1, 2006.
Revised May 2, 2006.
Accepted for publication May 3, 2006.
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 Ki values for DVS of 40.2 ± 1.6 and 558.4 ± 121.6 nM, respectively. DVS showed weak binding affinity (62% inhibition at 100 µM) at the human dopamine (DA) transporter. Inhibition of 3[H]5-HT or 3[H]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 µM), examined at a large number of non-transporter 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-HT1A autoreceptors, a 5-HT1A antagonist, WAY-100635 (0.3 mg/kg, subcutaneously), 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 novel and selective 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.
Key words:
SNRI, desvenlafaxine succinate, dopamine, momoamine transporters, norepinephrine, serotonin
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