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NEUROPHARMACOLOGY

Desvenlafaxine Succinate Identifies Novel Antagonist Binding Determinants in the Human Norepinephrine Transporter

Departments of Pharmacology (J.N.M., R.J.R., R.D.B.) and Psychiatry (R.D.B.) and Center for Molecular Neuroscience (R.D.B.), Vanderbilt University School of Medicine, Nashville, Tennessee; and Women's Health Research (D.C.D., R.C.W.) and Chemical and Screening Sciences (G.S., P.E.M., E.T.), Wyeth Pharmaceuticals, Collegeville, Pennsylvania

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 [³H]nisoxetine (NIS) binding. Using hNET in transfected human embryonic kidney-293 cells, this difference in potency for DVS at sites labeled by [³H]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 3-(4-iodophenyl)tropane-2-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.

Address correspondence to: Dr. Randy D. Blakely, Center for Molecular Neuroscience, Suite 7140 MRBIII, Nashville, TN 37232-8548. E-mail: randy.blakely{at}vanderbilt.edu

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