Desvenlafaxine Succinate: A New Serotonin and Norepinephrine Reuptake Inhibitor

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 Ϯ 1.6 and 558.4 Ϯ 121.6 nM, respectively. DVS showed weak binding affinity (62% inhibition at 100 M) at the human dopamine (DA) transporter. Inhibition of , 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-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.Biogenic amines such as serotonin (5-HT), norepinephrine (NE), and dopamine (DA) are neurotransmitters found in areas of the central nervous system (CNS) known to be important for regulation of cognitive function, mood, thermoregulation, pain sensation, sexual function, and various aspects of endocrine function related to homeostasis. Their synthesis is highly regulated, and long-term disturbance of the regulatory pathways for these neurotransmitters may lead to disruptions in overall health and quality of life. As with any specific mechanism that controls a physiological process, regulation of these neurotransmitters is a target of many pharmacological agents. Agents that have been developed to modulate these key neurotransmitters are well characterized and have provided evidence that regulation of these neurotransmitters affects physiological outcomes specific to each neurotransmitter. There are multiple means of regulating these neurotransmitters. One means is by inhibiting their presynaptic reuptake. Monoamine reuptake inhibitors work by binding to their respective transporter proteins located presynaptically. This binding interaction results in an increase in elimination time of the neurotransmitter cycle; thus, the extracellular concentration of the neurotransmitters increases in the synaptic cleft. This increase in neurotransmitter in the cleft allows for increased downstream cellular signaling (Blakely and Bauman, 2000). Serotonin and norepinephrine reuptake inhibitors (SNRIs) work by blocking the presynaptic reuptake of 5-HT and NE, resulting in an increased sustained level of both of these neurotransmitters. The 5-HT a...

Effect of Food on the Pharmacokinetics of Desvenlafaxine in Healthy Subjects

“…Like venlafaxine, desvenlafaxine has little effect on dopamine reuptake and primarily inhibits the reuptake of serotonin (5-HT) and norepinephrine (NE) [1,3,4]. Desvenlafaxine has a unique selectivity ratio for the 5-HT and NE transporters [3,4]; however, the clinical implications of this have not yet been determined. Desvenlafaxine has no monoamine oxidase activity and does not substantially interact with H 1 -histaminergic, muscarinic, or α 1 -adrenergic receptors [1,4].…”

“…Desvenlafaxine has a unique selectivity ratio for the 5-HT and NE transporters [3,4]; however, the clinical implications of this have not yet been determined. Desvenlafaxine has no monoamine oxidase activity and does not substantially interact with H 1 -histaminergic, muscarinic, or α 1 -adrenergic receptors [1,4].…”

“…Desvenlafaxine is approved for the treatment of major depressive disorder (MDD) [2]. Like venlafaxine, desvenlafaxine has little effect on dopamine reuptake and primarily inhibits the reuptake of serotonin (5-HT) and norepinephrine (NE) [1,3,4]. Desvenlafaxine has a unique selectivity ratio for the 5-HT and NE transporters [3,4]; however, the clinical implications of this have not yet been determined.…”

Desvenlafaxine in the treatment of major depressive disorder

“…In vitro functional assays indicate that DVS is approximately 10-fold more potent as an inhibitor of 5-HT uptake than NE uptake. [22][23][24] Affi nity for muscarinic, cholinergic, histamine H 1 −, and alpha 1 adrenergic receptors is very low. 22,23 DVS increases extracellular levels of both NE and 5-HT without increasing DA levels in the hypothalamus of ovariectomized rats.…”

Crystal structure of desvenlafaxinium 3,5-dinitrobenzoate 3,5-dinitrobenzoic acid monohydrate, C30H35N5O15

“…Desvenlafaxine -also known as O-desmethylvenlafaxine -isan antidepressant of the serotonin-norepinephrine re-uptake inhibitorclass [1]. Desvenlafaxine is asynthetic formofthe major active metabolite of venlafaxine and is being investigated as the first non-hormonal based treatment for menopause.…”