WY 45233 succinate

Desvenlafaxine succinate identifies novel antagonist binding determinants in the human norepinephrine transporter.[Pubmed:17673606]

J Pharmacol Exp Ther. 2007 Nov;323(2):720-9.

Desvenlafaxine succinate (DVS) is a recently introduced antagonist of the human norepinephrine and serotonin transporters (hNET and hSERT, respectively), currently in clinical development for use in the treatment of major depressive disorder and vasomotor symptoms associated with menopause. Initial evaluation of the pharmacological properties of DVS (J Pharmacol Exp Ther 318:657-665, 2006) revealed significantly reduced potency for the hNET expressed in membranes compared with whole cells when competing for [(3)H]nisoxetine (NIS) binding. Using hNET in transfected human embryonic kidney-293 cells, this difference in potency for DVS at sites labeled by [(3)H]NIS was found to distinguish DVS, the DVS analog rac-(1-[1-(3-chloro-phenyl)-2-(4-methylpiperazin-1-yl)-ethyl]cyclohexanol (WY-46824), methylphenidate, and the cocaine analog 3beta-(4-iodophenyl)tropane-2beta-carboxylic acid methyl ester (RTI-55) from other hNET antagonists, such as NIS, mazindol, tricyclic antidepressants, and cocaine. These differences seem not to arise from preparation-specific perturbations of ligand intrinsic affinity or antagonist-specific surface trafficking but rather from protein conformational alterations that perturb the relationships between distinct hNET binding sites. In an initial search for molecular features that differentially define antagonist binding determinants, we document that Val148 in hNET transmembrane domain 3 selectively disrupts NIS binding but not that of DVS.

Desvenlafaxine succinate: A new serotonin and norepinephrine reuptake inhibitor.[Pubmed:16675639]

J Pharmacol Exp Ther. 2006 Aug;318(2):657-65.

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.

Pharmacokinetic and pharmacodynamic profiles of the novel serotonin and norepinephrine reuptake inhibitor desvenlafaxine succinate in ovariectomized Sprague-Dawley rats.[Pubmed:16764833]

Brain Res. 2006 Jul 7;1098(1):71-8.

Desvenlafaxine succinate (DVS) is a novel serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor (SNRI) that is currently in clinical development for the treatment of major depressive disorder and vasomotor symptoms associated with menopause. Previous studies have documented the pharmacokinetic and pharmacodynamic profiles of DVS in male rats. Similar studies, however, have not been performed in ovariectomized (OVX) rats, a model that mimics the loss of ovarian hormones that occurs at menopause. The goal of the present study, therefore, was to characterize the pharmacokinetic and pharmacodynamic properties of DVS in OVX rats. Desvenlafaxine levels peaked in plasma, brain (total brain minus hypothalamus) and hypothalamus at concentrations of 7.0, 10.8 and 9.5 microM (assuming 1 g = 1 ml), respectively, 30 min post-dosing DVS (30 mg/kg, oral). The apparent terminal half-lives of desvenlafaxine in plasma, brain and hypothalamus were 3.0, 2.1 and 2.5 h, respectively. Based on AUC(0-last), brain to plasma and hypothalamus to plasma ratios were 1.7 and 1.3, respectively. Microdialysis experiments in the medial preoptic area of the hypothalamus showed that DVS (30 mg/kg, s.c.), in the presence of WAY-100635 (5-HT(1A) antagonist), increased 5-HT levels 225% at 1 h post-dosing. Norepinephrine levels increased 44% at 3 h post-dosing while dopamine levels were unchanged. Thus, in OVX rats, DVS has good pharmacokinetic properties, rapid brain penetration, excellent brain penetrability and selectively increases 5-HT and NE levels in the hypothalamus. This work supports the notion that DVS could have utility for treating disorders in menopausal women in which changes in 5-HT and/or NE have been implicated.